Alpha-heterocycle substituted tolunitriles

ABSTRACT

The invention is concerned with aromatase inhibiting compounds of formula I ##STR1## wherein R and Ro represent hydrogen or lower alkyl; or R and Ro located on adjacent carbon atoms and together when combined with the benzene ring to which they are attached form a naphthalene or tetrahydronaphthalene ring; R 1  and R 2  independently represent hydrogen, lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio, lower alkenyl, aryl, aryl-lower alkyl, C 3  -C 6  -cycloalkyl, or C 3  -C 6  -cycloalkyl-lower alkyl; or R 1  and R 2  combined represent lower alkylidene, mono- or di-aryl-lower alkylidene; R 1  and R 2  combined also represent C 4  -C 6  -straight chain alkylene, lower alkyl-substituted straight chain alkylene or ortho-phenylene bridged-C 2  -C 4  -straight chain alkylene, each forming with the carbon atom attached thereto a corresponding optionally substituted or benzo-fused 5, 6 or 7-membered ring; W represents 1-imidazolyl, 1-(1,2,4- or 1,3,4)-triazolyl or 3-pyridyl; or W represents 1-imidazolyl, 1-(1,2,4 or 1,3,4)-triazolyl or 3-pyridyl substituted by lower alkyl; and pharmaceutically acceptable salts thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of applicationSer. No. 240,862, filed Sep. 6, 1988, now U.S. Pat. 4,978,672 which is acontinuation-in-part application of application Ser. No. 164,696, filedMar. 7, 1988, now U.S. Pat. No. 4,937,250, which is a divisionalapplication of application Ser. No. 837,489 filed Mar. 7, 1986, now U.S.Pat. No. 4,749,713.

SUMMARY OF THE INVENTION

The invention relates to certain heterocycle-substituted tolunitrilesand derivatives described herein having valuable pharmacologicalproperties, particularly as aromatase inhibitors, to pharmaceuticalcompositions containing same, to the use of such heterocycle-substitutedtolunitriles for inhibiting aromatase activity and suppressing estrogensynthesis in mammals and for treating conditions responsive to aromataseinhibition and to inhibition of estrogen biosynthesis in mammals.

The compounds of the invention are active and useful as aromataseinhibitors in mammals. The compounds of the invention are therefore alsouseful, when administered alone or in combination to mammals asinhibitors of estrogen synthesis and for the treatment and ameliorationof estrogen dependent conditions, e.g. gynecomastia, mammary andendometrial tumors, endometriosis and premature labor; they are furtheruseful as anti-fertility agents.

Furthermore, the compounds of the invention are useful for delayingproestrus and estrus and preventing estrus in animals.

DETAILED DESCRIPTION OF THE INVENTION

Particularly the invention relates to the aromatase inhibiting compoundsof formula I ##STR2## wherein R and Ro represent hydrogen or loweralkyl; or R and Ro located on adjacent carbon atoms and together whencombined with the benzene ring to which they are attached form anaphthalene or tetrahydronaphthalene ring; R₁ and R₂ independentlyrepresent hydrogen, lower alkyl, (lower alkyl, aryl or aryl-loweralkyl)-thio, lower alkenyl, aryl, aryl-lower alkyl, C₃ -C₆ -cycloalkyl,or C₃ -C₆ -cycloalkyl-lower alkyl; or R₁ and R₂ combined represent loweralkylidene, mono- or di-aryl-lower alkylidene; R₁ and R₂ combined alsorepresent C₄ -C₆ -straight chain alkylene, lower alkyl-substitutedstraight chain alkylene or ortho-phenylene bridged-C₂ -C₄ -straightchain alkylene, each forming with the carbon atom attached thereto acorresponding optionally substituted or benzo-fused 5, 6 or 7-memberedring; W represents 1-imidazolyl, 1-(1,2,4- or 1,3,4)-triazolyl or3-pyridyl; or W represents 1-imidazolyl, 1-(1,2,4 or 1,3,4)-triazolyl or3-pyridyl substituted by lower alkyl; and pharmaceutically acceptablesalts thereof.

A specific embodiment of the invention relates to the compounds offormula I wherein W represents 1-imidazolyl or 1-imidazolyl substitutedby lower alkyl; another embodiment relates to the compounds of formula Iwherein W represents 1-(1,2,4- or 1,3,4-)-triazolyl or 1-(1,2,4- or or1,3,4-)-triazolyl substituted by lower alkyl; a further embodimentrelates to the compounds of formula I wherein W represents 3-pyridyl or3-pyridyl substituted by lower alkyl. Further particular embodimentsrelate to compounds of formula I wherein R and Ro represent hydrogen orlower alkyl; also those wherein R and Ro together with the benzene ringto which they are attached form a naphthalene or tetrahydronaphthalenering.

Preferred are the compounds of formula I wherein the ##STR3## groupingis attached para to the cyano group.

Preferred are the said compounds of formula I wherein R and Ro representhydrogen or lower alkyl; or R and Ro located on adjacent carbon atomsand together when combined with the benzene ring to which they areattached form a naphthalene or tetrahydronaphthalene ring; R₁ representshydrogen, lower alkyl, aryl, aryl-lower alkyl or lower alkenyl; R₂represents hydrogen, lower alkyl, aryl, aryl-lower alkyl, (lower alkyl,aryl or aryl-lower alkyl)-thio or lower alkenyl; or R₁ and R₂ combinedrepresent lower alkylidene or C₄ -C₆ -alkylene; W has meaning givenabove; and aryl within the above definitions represents phenyl or phenylsubstituted by one or two substituents selected from lower alkyl, loweralkoxy, hydroxy, acyloxy, nitro, amino, halogen, trifluoromethyl, cyano,carboxy, carboxy functionalized in form of a pharmaceutically acceptableester or amide, lower alkanoyl, aroyl, lower alkylsulfonyl, sulfamoyl,N-lower alkylsulfamoyl or N,N-di-lower alkylsulfamoyl; or aryl withinthe above definitions also represents a heterocyclic aromatic radicalselected from thienyl, indolyl, pyridyl and furyl, or a saidheterocyclic radical monosubstituted by lower alkyl, lower alkoxy, cyanoor halogen; and pharmaceutically acceptable salts thereof.

An embodiment relates to the compounds of formula I wherein R and Rorepresent hydrogen or lower alkyl; or R and Ro located on adjacentcarbon atoms and together when combined with the benzene ring to whichthey are attached form a naphthalene or tetrahydronaphthalene ring; R₁represents hydrogen; R₂ represents hydrogen, lower alkyl, lower alkenyl,aryl, aryl-lower alkyl, C₃ -C₆ -cycloalkyl, or C₃ -C₆ -cycloalkyl-loweralkyl; or R₁ and R₂ combined represent lower alkylidene, or mono- ordi-aryl-lower alkylidene; R₁ and R₂ combined also represent C₄ -C₆-straight chain alkylene, lower alkyl-substituted straight chainalkylene or ortho phenylene bridged-C -C₄ -straight chain alkylene toform with the carbon atom attached thereto a corresponding optionallysubstituted or benzo-fused 5, 6 or 7-membered ring; W represents1-imidazolyl, 1-(1,2,4- or 1,3,4)-triazolyl or 3-pyridyl; or Wrepresents 1-imidazolyl, 1-(1,2,4 or 1,3,4)-triazolyl or 3-pyridylsubstituted by lower alkyl; or a pharmaceutically acceptable saltthereof.

Another embodiment relates to the compounds of formula I wherein R andRo represent hydrogen or lower alkyl; or R and Ro located on adjacentcarbon atoms and together when combined with the benzene ring to whichthey are attached form a naphthalene or tetrahydronaphthalene ring; R₁represents hydrogen; R₂ represents hydrogen, lower alkyl, aryl,aryl-lower alkyl, or lower alkenyl; or R₁ and R₂ combined representlower alkylidene or C₄ --C₆ -alkylene; W represents 1-imidazolyl or1-imidazolyl substituted by lower alkyl; and aryl within the abovedefinitions represents phenyl or phenyl substituted by one or twosubstituents selected from lower alkyl, lower alkoxy, hydroxy, acyloxy,nitro, amino, halogen, trifluoromethyl, cyano, carboxy, carboxyfunctionalized in form of a pharmaceutically acceptable ester or amide,lower alkanoyl(aroyl, lower alkylsulfonyl, sulfamoyl, N-loweralkylsulfamoyl or N,N-di-lower alkylsulfamoyl; or aryl within the abovedefinitions also represents a heterocyclic aromatic radical selectedfrom thienyl, indolyl, pyridyl and furyl, or a said heterocyclic radicalmonosubstituted by lower alkyl, lower alkoxy, cyano or halogen; or apharmaceutically acceptable salt thereof.

Particularly preferred are the above compounds of formula I wherein R₁represents hydrogen; and W, R, Ro, R₂ as well as R₁ and R₂ combined havemeaning as defined above.

Further preferred are the compounds of formula II ##STR4## wherein R₁ 'represents hydrogen; R₂ ' represents hydrogen, lower alkyl, phenyl,pyridyl, thienyl or benzyl; or R₂ ' represents phenyl or benzyl, eachmonosubstituted on the phenyl ring by cyano, lower alkyl, lower alkoxy,hydroxy, lower alkanoyloxy, aroyloxy, nitro, halogen, trifluoromethyl,lower alkanoyl, aroyl, lower alkylsulfonyl, carbamoyl, N-mono-orN,N-di-lower alkylcarbamoyl, sulfamoyl, N-mono- or N,N-di-loweralkylsulfamoyl; or R₁ ' and R₂ ' combined represent together loweralkylidene, benzylidene or diphenylmethylidene; or R₁ ' and R₂ 'combined represent together C₄ -C₆ straight chain alkylene; R₃represents hydrogen or lower alkyl; and pharmaceutically acceptablesalts thereof.

Particularly preferred are the compounds of formula II wherein R₁ 'represents hydrogen; R₂ ' represents hydrogen, lower alkyl, pyridyl,benzyl or phenyl; or R₂ ' represents benzyl or phenyl, eachmonosubstituted on phenyl by cyano, lower alkyl, lower alkoxy, hydroxy,lower alkanoyloxy, halogen, nitro, trifluoromethyl, lower alkanoyl,aroyl, lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-loweralkylcarbamoyl, sulfamoyl, N-mono- or N,N-di-lower alkylsulfamoyl; R₃represents hydrogen or lower alkyl; and pharmaceutically acceptablesalts thereof.

Preferred in turn are the compounds of formula II wherein R₁ 'represents hydrogen; R₂ ' represents hydrogen, lower alkyl, benzyl,phenyl, or 3- or 4-pyridyl; or R₂ ' represents phenyl or benzyl, eachmonosubstituted on phenyl by cyano, halogen, lower alkoxy, lower alkylor trifluoromethyl; R₃ represents hydrogen or lower alkyl at the 4 or 5position; and pharmaceutically acceptable salts thereof.

Particularly preferred are the compounds of formula II wherein R₂ 'represents unsubstituted or monosubstituted phenyl or benzyl, orpyridyl, as defined hereinabove.

Most preferred are the compounds of formula III ##STR5## wherein R₂ 'represents 3-pyridyl, p-cyanobenzyl or p-cyanophenyl; andpharmaceutically acceptable salts thereof.

A particular embodiment of the invention relates to the compounds offormula I wherein R and Ro are located on adjacent carbon atoms andtogether when combined with the benzene ring to which they are attachedform a naphthalene or tetrahydronaphthalene ring.

A preferred embodiment thereof relates to the naphthonitriles of formulaIV ##STR6## wherein R₁ ' represents hydrogen; R₂ ' represents hydrogen,lower alkyl, phenyl, lower alkylthio, phenyl-lower alkylthio,phenylthio, pyridyl, thienyl or benzyl; or R₂ ' represents phenyl,phenyl-lower alkylthio, phenylthio or benzyl, each monosubstituted onthe phenyl ring by cyano, lower alkyl, lower alkoxy, hydroxy, loweralkanoyloxy, aroyloxy, nitro, halogen, trifluoromethyl, lower alkanoyl,aroyl, lower alkylsulfonyl, carbamoyl, N-mono-or N,N-di-loweralkylcarbamoyl, sulfamoyl, N-mono- or N,N-di-lower alkylsulfamoyl; or R₁' and R₂ ' combined represent together lower alkylidene, benzylidene,diphenylmethylidene; or R₁ ' and R₂ ' combined represent together C₄ -C₆straight chain alkylene; R₃ represents hydrogen or lower alkyl; andpharmaceutically acceptable salts thereof.

Particularly preferred are the compounds of formula IV wherein R₁ 'represents hydrogen; R₂ ' represents hydrogen, lower alkyl, pyridyl; orR₂ ' represents benzyl or phenyl, each unsubstituted or monosubstitutedon phenyl by cyano, lower alkyl, lower alkoxy, hydroxy, loweralkanoyloxy, halogen, nitro, trifluoromethyl, lower alkanoyl, aroyl,lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl,sulfamoyl, N-mono or N,N-di-lower alkylsulfamoyl; R₃ represents hydrogenor lower alkyl; and pharmaceutically acceptable salts thereof.

Preferred in turn are the compounds of formula IV wherein R₁ 'represents hydrogen; R₂ ' represents hydrogen, lower alkyl, benzyl,phenyl, or 3 or 4-pyridyl; or R₂ ' represents phenyl or benzyl, eachmonosubstituted on phenyl by cyano, halogen, lower alkoxy, lower alkylor trifluoromethyl; R₃ represents hydrogen or lower alkyl at the 4 or 5position; and pharmaceutically acceptable salts thereof.

Most preferred are the compounds of formula IV wherein R₁ ' and R₃represent hydrogen; R₂ represents 3-pyridyl, p-cyanobenzyl orp-cyanophenyl; and pharmaceutically acceptable salts thereof.

Another specific preferred embodiment of the invention relates tocompounds of formula I wherein W represents 1-(1,2,4)-triazolyl or1-(1,2,4)-triazolyl substituted by lower alkyl, namely the compounds offormula V ##STR7## wherein R₁ ' represents hydrogen; R₂ ' representshydrogen, lower alkyl, phenyl, pyridyl, thienyl or benzyl; or R₂ 'represents phenyl or benzyl, each monosubstituted on the phenyl ring bycyano, lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, aroyloxy,nitro, halogen, trifluoromethyl, lower alkanoyl, aroyl, loweralkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl,sulfamoyl, N-mono- or N,N-di-lower alkylsulfamoyl; or R₁ ' and R₂ 'combined represent together lower alkylidene, benzylidene ordiphenylmethylidene; or R₁ ' and R₂ ' combined represent together C₄ -C₆straight chain alkylene; R₃ ' represents hydrogen or lower alkyl; andpharmaceutically acceptable salts thereof.

Particularly preferred are the compounds of formula V wherein R₁ 'represents hydrogen; R₂ ' represents hydrogen, lower alkyl, pyridyl; orR₂ ' represents benzyl or phenyl, each unsubstituted or monosubstitutedon phenyl by cyano, lower alkyl, lower alkoxy, hydroxy, loweralkanoyloxy, halogen, nitro, trifluoromethyl, lower alkanoyl, aroyl,lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl,sulfamoyl, N-mono- or N,N-di-lower alkylsulfamoyl; R₃ representshydrogen or lower alkyl; and pharmaceutically acceptable salts thereof.

Preferred in turn are the compounds of formula V wherein R₁ ' representshydrogen; R₂ represents hydrogen, lower alkyl, benzyl, phenyl, or 3- or4-pyridyl; or R₂ ' represents phenyl or benzyl, each monosubstituted onphenyl by cyano, halogen, lower alkoxy, lower alkyl or trifluoromethyl;R₃ ' represents hydrogen or lower alkyl; and pharmaceutically acceptablesalts thereof.

Most preferred are the compounds of formula V where R₁ ' and R₃ 'represent hydrogen; R₂ ' represents 3-pyridyl, p-cyanobenzyl orp-cyanophenyl; and pharmaceutically acceptable salts thereof.

A further specific embodiment of the invention relates to compounds ofthe formula I wherein W represents a 3-pyridyl group, particularly thecompounds of formula VI ##STR8## wherein R₁ ' represents hydrogen; R₂ 'represents hydrogen, lower alkyl, phenyl, lower alkylthio, phenyl-loweralkylthio, phenylthio, pyridyl, thienyl, benzyl; or R₂ ' representsphenyl, phenyl-lower alkylthio, phenylthio or benzyl eachmonosubstituted on the phenyl ring by cyano, lower alkyl, lower alkoxy,hydroxy, lower alkanoyloxy, aroyloxy, nitro, halogen, trifluoromethyl,lower alkanoyl, aroyl, lower alkylsulfonyl, carbamoyl, N-mono- orN,N-di-lower alkylcarbamoyl, sulfamoyl, N-mono- or N,N-di-loweralkylsulfamoyl; or R₁ ' and R₂ ' combined represent together loweralkylidene, benzylidene or diphenylmethylidene; or R₁ ' and R₂ 'combined represent together C₄ -C₆ straight chain alkylene; R₃represents hydrogen or lower alkyl; and pharmaceutically acceptablesalts thereof.

Particularly preferred are the compounds of formula VI wherein R₁ 'represents hydrogen; R₂ ' represents hydrogen, lower alkyl, pyridyl; orR₂ ' represents benzyl or phenyl each unsubstituted or monosubstitutedon phenyl by cyano, lower alkyl, lower alkoxy, hydroxy, loweralkanoyloxy, halogen, nitro, trifluoromethyl, lower alkanoyl, aroyl,lower alkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkyl-carbamoyl,sulfamoyl, N-mono or N,N-di-lower alkylsulfa-moyl; R₃ representshydrogen or lower alkyl; and pharmaceutically acceptable salts thereof.

Preferred in turn are the compounds of formula VI wherein R₁ ' and R₃represent hydrogen; R₂ ' represents hydrogen, lower alkyl, benzyl,phenyl, or 3- or 4-pyridyl; or R₂ ' represents phenyl or benzyl eachsubstituted on phenyl by cyano, halogen, lower alkoxy, lower alkyl ortrifluoromethyl; and pharmaceutically acceptable salts thereof.

Most preferred are the compounds of formula VI wherein R₁ ' and R₃represent hydrogen; R₂ ' represents 3- or 4-pyridyl, p-cyanobenzyl orp-cyanophenyl; and pharmaceutically acceptable salts thereof.

The general definitions used herein, unless denoted otherwise, have thefollowing meanings within the scope of the present invention.

The term "lower" referred to above and hereinafter in connection withorganic radicals or compounds respectively defines such with up to andincluding 7, preferably up to and including 4 and advantageously one ortwo carbon atoms.

A lower alkyl group preferably contains 1-4 carbon atoms and representsfor example ethyl, propyl, butyl or advantageously methyl.

A lower alkenyl group preferably contains 1-4 carbon atoms andrepresents for example allyl or crotyl.

A lower alkoxy group preferably contains 1-4 carbon atoms and representsfor example methoxy, propoxy, isopropoxy or advantageously ethoxy.

Halogen preferably represents chlorine, but may also be bromine,fluorine or iodine.

Acyl in acyloxy represents lower alkanoyl, aroyl, lower alkoxycarbonyl,or N,N-di-lower alkylcarbamoyl, preferably lower alkanoyl.

Lower alkanoyl is preferably acetyl, propionyl, butyryl, or pivaloyl.

Aroyl is preferably benzoyl or benzoyl substituted by one or two oflower alkyl, lower alkoxy, halogen or trifluoromethyl; aroyl is alsothienoyl, pyrroloyl, 2-, 3- or 4-pyridylcarbonyl, advantageouslynicotinoyl.

Lower alkanoyloxy is preferably acetoxy, pivaloyloxy or propionyloxy.

Aroyloxy is preferably benzoyloxy or benzoyloxy substituted on thebenzene ring by one or two of lower alkyl, lower alkoxy, halogen ortrifluoromethyl.

Heteroaroyloxy is preferably 2-, 3- or 4-pyridylcarbonyloxy,advantageously nicotinoyloxy.

Aryl represents a carbocyclic or heterocyclic aromatic radicalcomprising optionally substituted phenyl, naphthyl, pyridyl, thienyl,indolyl or furyl.

A carbocyclic aromatic radical represents preferably phenyl or phenylsubstituted by one or two substituents selected from lower alkyl, loweralkoxy, hydroxy, acyloxy, nitro, amino, halogen, trifluoromethyl, cyano,carboxy, carboxy functionalized in form of a pharmaceutically acceptableester or amide, lower alkanoyl, aroyl, lower alkylsulfonyl, sulfamoyl,N-lower alkylsulfamoyl and N,N-di-lower alkylsulfamoyl; also 1- or2-naphthyl, optionally substituted by lower alkyl, lower alkoxy, cyanoor halogen.

A heterocyclic aromatic radical represents particularly thienyl,indolyl, pyridyl, furyl or a said heterocyclic radical optionallymono-substituted by lower alkyl, lower alkoxy , cyano or halogen.

Thienyl represents 2- or 3-thienyl, preferably 2-thienyl.

Pyridyl represents 2-, 3- or 4- pyridyl, preferably 3- or 4-pyridyladvantageously 3-pyridyl.

Furyl represents 2- or 3-furyl, preferably 3-furyl.

Indolyl represents preferably 3-indolyl.

Carboxy functionalized in form of a pharmaceutically acceptable esterrepresents preferably lower alkoxycarbonyl; aryl-lower alkoxycarbonyl,e.g. benzyloxycarbonyl or pyridylmethoxycarbonyl; loweralkanoyloxy-substituted lower alkoxycarbonyl, e.g.pivaloyloxymethoxycarbonyl; or 3-phthalidoxycarbonyl.

Carboxy functionalized in form of a pharmaceutically acceptable amiderepresents preferably carbamoyl, N-mono-lower alkylcarbamoyl orN,N-di-lower alkylcarbamoyl.

Aryl-lower alkyl represents preferably arylmethyl or arylethyl in whicharyl represents a carbocyclic or heterocyclic aromatic radical asdefined above, advantageously optionally substituted phenyl as definedabove.

Lower alkylidene represents preferably straight chain lower alkylidene,advantageously methylidene or ethylidene.

C₄ -C₆ -alkylene represents advantageously butylene or pentylene.

Ortho-phenylene bridged-C₂ -C₄ - straight chain alkylene represents C₂-C₄ -straight chain alkylene interrupted by ortho-phenylene, preferablyortho-phenylene bridged CH₂ CH₂.

C₃ -C₆ -cycloalkyl represents preferably cyclopentyl or cyclohexyl.

Pharmaceutically acceptable salts represent acid addition salts withconventional acids, for example mineral acids, e.g. hydrochloric acid,sulfuric or phosphoric acid, or organic acids, for example aliphatic oraromatic carboxylic or sulfonic acids, e.g. acetic, propionic, succinic,glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric,hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic,anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic,gluconic, nicotinic, methanesulfonic, ethanesulfonic,halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic orcyclohexylsulfamic acid; also amino acids, such as arginine and lysine.For compounds of the invention having acidic groups, for example a freecarboxy group, pharmaceutically acceptable salts also represent metal orammonium salts, such as alkali metal or alkaline earth metal salts, e.g.sodium, potassium, magnesium or calcium salts, as well as ammoniumsalts, which are formed with ammonia or suitable organic amines.

The compounds of the invention which possess an asymmetric carbon atomexist as racemates and the R and S enantiomers thereof. The presentinvention is intended to include these forms, also diastereoisomers andmixtures thereof if two or more asymmetric centers are present, as wellas geometric isomers, e.g. cis and trans isomers if a double bond ispresent in the molecule.

The compounds of the instant invention have valuable pharmacologicalproperties. For example, they are useful as inhibitors of aromataseactivity and inhibitors o estrogen biosynthesis in mammals, and fortreating conditions responsive thereto. These compounds inhibit themetabolic conversion of androgens to estrogens in mammals. Thus, thecompounds of formula I are useful e.g. in the treatment of gynecomastia,i.e. male breast development, by inhibiting the aromatization ofsteroids in males susceptible to this condition. Moreover, the compoundsof formula I are useful e.g. in the treatment of estrogen dependentdiseases in females, for example estrogen dependent female breastcancer, especially in postmenopausal females, by inhibiting estrogenbiosynthesis. These effects are demonstrable in in vitro assay tests orin vivo animal tests using advantageously mammals, e.g. guinea pigs,mice, rats, cats, dogs, or monkeys. Additionally, the compounds offormula I are useful e.g. in the prevention of fertility in femalemammals; i.e. the prevention of ovulation and implantation. The applieddosage may range between about 0.001 and 30 mg/Kg, preferably betweenabout 0.001 to 5 mg/Kg.

The in vitro inhibition of aromatase activity of the compounds of thepresent invention can be demonstrated as follows:

A microsomal fraction is prepared from human placenta by the methodessentially as described by Thompson and Siiteri, J. Biol. Chem., Vol.249, p. 5364 (1974). The microsomal preparation so obtained islyophilized and stored at -40° C.

The assay is conducted substantially as described by Thompson andSiiteri. The human placental microsomes are added to [1,2-³H]-androstenedione and incubated for 20 minutes at 37° C. The amount ofaromatization of the labelled substrate is detected by the loss of ³ H₂O into the incubation medium. The substrate is removed by chloroformextraction, followed by adsorption to charcoal in suspension. Thecharcoal is removed by centrifugation and the steroid-free medium iscounted in a liquid scintillation counter. Compounds are tested foraromatase inhibitory activity by adding them to the incubation mediumprior to the addition of the microsomes. The relative cpm obtained withand without the inhibitor is used to calculate the percent inhibition ofthe aromatization of androstenedione to estrone. IC₅₀ values can bedetermined graphically as the concentration of test compound at whichthe aromatization of androstenedione to estrone is reduced to 50% ofcontrol value.

The compounds of the invention are effective at concentrations rangingfrom about 10⁷ M to about 10⁻⁹ M. Illustrative of the invention thecompounds of examples 1a, 1c, 2a, 5e and 11f have an IC₅₀ of about 10,1.5, 1.2, 16 and 3 nanomolar, respectively, in the in vitro assay foraromatase inhibition; also the compound of example 20a has an IC₅₀ ofabout 11 nanomolar.

The in vivo inhibition of aromatase activity of the compounds of thepresent invention can be demonstrated as follows, by measuring theinhibition of estrogen synthesis in rats.

Twenty-one-day-old female rats are injected subcutaneously with 10 IUpregnant mare serum gonadotropin (PMS). Two days later the same rats areinjected subcutaneously with 30 IU human chorionic gonadrotropin (hCG).On the day following the hCG treatment the rats are injectedsubcutaneously with either propylene glycol (0.2 ml; p.o.) or withvarious doses of the test compound. One hour later all of the rats aretreated with 2.25 mg androstenedione in 0.1 ml oil, subcutaneously. Fourhours after the injection of androstenedione the rats are sacrificed andtheir ovaries removed and trimmed free of adhering tissue and stored inpairs at -40° C. To determine the total estrogen content of the ovaries,1.5 ml of 0.05M aqueous potassium phosphate buffer, pH 7.4, and 0.2 mlof 0.1N aqueous sodium hydroxide are added to the tissues which are thenhomogenized. The homogenate is extracted with 15 ml of diethyl ether, 5ml aliquots are radioimmunoassayed with antiserum having 100% crossreactivity with estrone, estradiol and estriol. The ovarian estrogencontent is expressed as ng estrogen/pair of ovaries. The inhibition ofestrogen synthesis, indicative of aromatase inhibition, is calculatedfrom the ovarian estrogen content in treated as compared to controlanimals.

Illustrative of the invention, the compound of Example 2a inhibitestrogen synthesis at a dose of about 1.5 ug/Kg p.o. in the female rat,and the compounds of examples 5e and 11f inhibit estrogen synthesis at adose of about 3 ug/Kg p.o.

The antitumor activity, especially in estrogen-dependent tumors, can bedemonstrated in vivo e.g. in dimethylbenzanthracene (DMBA)-inducedmammary tumors in female Sprague-Dawley rats [see Proc. Soc. Exp. Biol.Med. 160, 296-301 (1979)]. Compounds of the invention cause regressionof existing tumors and suppress the appearance of new tumors at dailydoses of about 0.01 to about 20 mg/kg p.o. Illustrative of theinvention, the compound of Example 2a is effective at a daily dose ofabout 0.1 mg/Kg p.o administered to rats; the compound of example 20a iseffective at a dose of about 0.03 mg/Kg p.o.

The in vivo antifertility property (e.g. inhibition of implantationand/or induction of fetal resorption) of the compounds of the presentinvention can be demonstrated as follows, by monitoring the implantationand/or fetal resorption in rats.

Mated female rats (Sprague Dawley) weighing approximately 180-200 g wereobtained on the day of coitus. The presence of sperm in the vagina wasused as a verification that mating had occurred. On the day of receipt,day of coitus or day 0 of `pregnancy`, the rats are divided into twogroups of six to eight rats per group. One group is given various dosesof the test compound p.o., suspended in 0.2 ml of carboxymethylcellulose(CMC) beginning on day 1 of `pregnancy` and continuing through day 9 of`pregnancy`. These same rats receive a daily injection of 0.1 ml ofsesame oil s.c. over this same time frame. The second group of ratsreceive the vehicles, CMC p.o. and oil s.c., on days 1-9 of `pregnancy`.All of the rats are sacrificed on day 12 or 13 of `pregnancy`, and theiruteri are exposed and examined for fetuses and/or resorption sites.

Illustrative of the invention, the compound of Example 2a administeredas the fumarate or hemisuccinate salt inhibits fertility at a dose ofabout 4 mg/Kg/p.o. in female rats.

Furthermore, the compounds of the invention are essentially devoid ofcholesterol side chain cleavage inhibitory activity and do not induceadrenal hypertrophy at effective aromatase inhibitory doses.

Additionally, the compounds of the present invention are useful indelaying proestrus and estrus and further in inhibiting estrus inanimals, especially in the dog (canine) and furthermore in the cat(feline).

Pet overpopulation continues to be a serious problem for which humansocieties have long sought a solution. For example, the attraction ofmale dogs and possible undesired mating of female dogs during estrus isa serious problem for many responsible pet owners. Surgicalovariohysterectomy is a final procedure with possible long termcomplications and is not in all cases an acceptable approach, especiallywhere the intent is only to delay estrus in field trial and show dogs orto delay breeding. In later cases, only a postponement of proestrus andestrus or temporary and reversible inhibition of estrus are desired.

Proestrus, for example in the bitch, commences with a vaginal discharge,followed by attraction of the male resulting from estrogen secretion andlasts on an average of 9 days. The females only permit mating duringestrus. The compounds of the present invention, when administered tofemale dogs e.g. on the second day of proestrus, terminate all physicalsigns of proestrus andestrus and mating will be prevented. Dogs inanestrus which have a known history of previous estrus cycles, matingand conception do not experience estrus during about 224 days ofadministration of compounds of the present invention.

For example, the cessation of proestrus and estrus, e.g. in the dog canbe demonstrated as follows: After initiating oral adminstration of acompound of the present invention to a female dog, the day afterproestrus is detected, the signs of proestrus are eliminated. After 10.0mg/kg p.o. daily of the compound of example 46 is administered the dogsrefused to accept a male dog 9 and 11 days following the initial sign ofproestrus. Likewise, when administering a compound of the presentinvention to a dog in the anestrus phase of the estrous cycle the dogsdo not experience estrus. For example, ten mature beagles duringanestrus with known breeding histories were administered e.g. 10.0 mg/kgp.o. daily of the compound of example 46 for 224 days. No signs ofproestrus were observed in these animals while all control dogsexhibited proestrus and estrus at least once. Ten female beagles withknown breeding histories were administered 10.0 mg/kg p.o. daily of thecompound of example 46 for 91 days beginning on the first day proestruswas noted. All signs of proestrus disappeared and no dogs accepted amale when presented 9 and 11 days later. Proestrus was not observedduring the remainder of the 91 days. During the 190 days recovery periodeight of ten dogs exhibited estrus.

Due to their pharmacological properties as selective aromataseinhibitors, the compounds of the invention are useful for the inhibitionof estrogen biosynthesis in mammals and the treatment of estrogendependent disorders responsive thereto, such as mammary tumors (breastcarcinoma), endometriosis, premature labor and endometrial tumors infemales, as well as gynecomastia in males.

Accordingly, the compounds of the present invention are useful indelaying proestrus and estrus and in inhibiting of proestrus in theanestrus animal, especially in the canine, and can thus be used as birthcontrol agents in the animal, especially in the canine.

As a consequence of the antifertility property of the compounds of thepresent invention, these compounds may find use not only in theantifertility uses generally thought of but may also find use inreducing rodent and other mammalian pest populations wherein thereproductive cycle is estrogen dependent.

The compounds of formula I or II-VI may be prepared as follows:

a) for compounds of formula I wherein W represents 1-imidazolyl or1-triazolyl each optionally substituted by lower alkyl, condensing acompound of the formula VII

    W'--H                                                      (VII)

wherein W' represents 1-imidazolyl or 1-triazolyl each optionallysubstituted by lower alkyl, or an N-protected derivative thereofparticularly where W represents 1-imidazolyl or loweralkyl-substituted-1-imidazolyl, with a reactive esterified derivative ofa compound of the formula VIII ##STR9## wherein R, Ro, R₁ and R₂ havemeaning as defined herein for formula I;

b) for compounds wherein W represents 3-pyridyl optionally substitutedby lower alkyl, dehalogenating a compound of the formula IX ##STR10##wherein W" represents 3-pyridyl optionally substituted by lower alkyl, Xrepresents halogen, preferably chloro, R and Ro have meaning as definedherein for compounds of formula I and R₁ has meaning as defined hereinfor formula I; and if required reacting the resulting product of formulaX ##STR11## with a reactive derivative of the radical R₂ using processc) below;

c) condensing under basic conditions a compound of the formula XI##STR12## (being a compound of formula I wherein R₁ and R₂ representhydrogen) wherein R, Ro and W have meaning as defined herein for formulaI, with a reactive functional derivative of a radical R₁ or R₂ (R₁ or R₂not representing hydrogen), so as to obtain a compound of formula Iwherein only one of R₁ and R₂ represents hydrogen; or similarlycondensing a compound of formula I so obtained with a reactivefunctional derivative of a radical R₁ or R₂ (R₁ or R₂ not representinghydrogen) to obtain a compound of formula I wherein neither R₁ nor R₂represents hydrogen; or condensing a compound of the formula XI with areactive bifunctional derivative of R₁ and R₂ combined representing C₄-C₆ straight alkylene, lower alkyl substituted C₄ -C₆ straight chainalkylene or 1,2-phenylene-bridged-C₂ -C₄ straight chain alkylene toobtain a corresponding compound of formula I;

d) converting R₅ to cyano in a compound of the formula XII ##STR13##wherein W, R, Ro, R₁ and R₂ have meaning as defined above and R₅represents a group or radical that can be converted to the cyano group;

e) converting a compound of formula I into another compound of formulaI; and/or converting a free compound into a salt, and/or converting asalt into a free compound or into another salt; and/or separating amixture of isomers or racemates into the single isomers or racematesand/or resolving a racemate into the optical isomers.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as carboxy, amino (including ring NH) and hydroxygroups, are optionally protected by conventional protecting groups thatare common in preparative organic chemistry. Protected carboxy, aminoand hydroxy groups are those that can be converted under mild conditionsinto free carboxy, amino and hydroxy groups without the molecularframework being destroyed or other undesired side reactions takingplace.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction components andunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (carboxy group, aminogroup, etc.), the structure and stability of the molecule of which thesubstituent is a part, and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, for example, in J. F. W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London, NewYork, 1973, T. W. Greene, "Protective Groups in Organic Synthesis",Wiley, New York, 1984,

Relating to the above processes, a reactive functional derivative of theradicals R₁ and R₂ represents said radicals substituted by a leavinggroup, preferably by lower alkyl- or aryl-sulfonyloxy, e.g. mesyloxy ortoluenesulfonlyloxy, or by halogen, e.g. fluoro, chloro, bromo or iodo.Similarly, a reactive esterified derivative of an alcohol, e.g. of acompound of formula VIII represents said alcohol esterified in the formof a leaving group, e.g. lower alkyl- or aryl-sulfonyloxy, such asmesyloxy or toluenesulfonyloxy, or halogen, such as chloro, bromo oriodo.

Protecting groups for the imidazolyl nitrogen are preferably tri-loweralkylsilyl, e.g. trimethylsilyl, lower alkanoyl, e.g. acetyl, di-loweralkylcarbamoyl such as dimethylcarbamoyl, or triarylmethyl, e.g.triphenylmethyl.

The condensation according to process (a) is carried out according toN-alkylation procedures well-known in the art, either as such or in thepresence of a base such as triethylamine or pyridine in an inertsolvent, e.g. dichloromethane, at room temperature or near the boilingof the solvent used.

In the case of protected imidazolyl, alkylation occurs on the secondunprotected nitrogen to first form a quaternary compound which isadvantageously simultaneously deprotected in situ prior to the isolationof the product. The imidazole and triazole starting materials of formulaVII are either known or are prepared according to methods known in theart.

The nitrile substituted starting materials representing reactiveesterified derivatives of the carbinols of formula VIII are also eitherknown or are prepared e.g. as illustrated below and the examples herein.For example, the halo substituted starting materials can beadvantageously prepared using the following illustrative sequence ofreactions using appropriate reaction conditions known in the art andillustrated in the examples. ##STR14##

The starting materials of formula XIV represent appropriate aldehydes orketones in which R₁ and R₂ correspond to relevant definitions in formulaI.

For compounds of formula I wherein R₁ represents hydrogen and R₂represents cyanophenyl, the intermediate corresponding to formula XV canbe advantageously prepared by reacting the lithium organometallicreagent of formula XIII with ethyl formate (instead of compound offormula XIV) in the above sequence of reactions.

It should also be noted that in the above intermediate XIII, theCONH-t-Bu substituent may be replaced by cyano or any other groupingsuitable for the condensation and known in the art to be convertibleinto cyano. Such groupings are included under process (d) (R₅ in formulaXII).

The dehalogenation under process (b) for the preparation of thecompounds of formula I wherein W represents pyridyl optionallysubstituted by lower alkyl can be achieved advantageously with zinc inacetic acid. Other suitable reagents include tributyl tin hydride oraluminum amalgam.

The starting halides of formula IX can be prepared from an alcohol witha halogenating agent, e.g. thionyl chloride as described under processa). The alcohol can in turn be prepared by condensation of a compound offormula XIII or the like with an appropriate aldehyde or ketone of theformula XVII ##STR15## in which R₁ and R₂ correspond to relevantdefinitions for R₁ and R₂ in formula I and W" represents 3-pyridyl.

The condensation according to process (c) is carried out according toprocedures generally known in the art for displacement e.g. of a halo,lower alkyl- or arylsulfonyloxy leaving group.

The condensation is carried out in a conventional manner by firstforming a carbanion in the presence of a strong base such as lithiumdiisopropylamide, an alkali metal hydride, an alkali metal alkoxide suchas potassium t-butoxide, or a strongly basic tertiary amine such as1,5-diazabicyclo[4.3.0]non-5-ene(DBN), preferably in an inertatmosphere, for example under nitrogen atmosphere and in a polar solventsuch as dimethylformamide.

For compounds of formula I wherein R₁ and/or R₂ represents p-cyanophenyla suitable reactive derivative is p-fluorobenzonitrile. For compoundswherein R₁ or R₂ represents (lower alkyl, aryl or aryl-loweralkyl)-thio, suitable reactive derivatives are the disulfidescorresponding thereto, such as diphenyl disulfide or dimethyl disulfide.

Process (d) is carried out according to known methods for theintroduction of a nitrile group.

A group or radical R₅ in a compound of formula XII which can beconverted into the CN group, is, for example, hydrogen, esterifiedhydroxy, for example halo, especially chloro, bromo, or iodo, or asulfonyloxy group, for example p-toluenesulfonyloxy, benzenesulfonyloxyor mesyloxy, sulfo, amino, carboxy, carboxy in the form of a functionalderivative, for example carbamoyl, lower alkylcarbamoyl, for examplet-butyl-carbamoyl, or haloformyl, for example chloro- or bromoformyl,formyl, a formyl group in the form of a functional derivative, forexample hydroxyiminomethyl,or a halomagnesium group, for example iodo-,bromo- or chloromagnesium.

Compounds of the formula I (or II-VI) can be obtained, for example, bycarrying out the following conversions:

The conversion of a compound of the formula XII wherein R₅ is hydrogen,to the corresponding nitrile of the formula I is performed e.g.according to the known method of C. Friedel, F. M. Crafts and P. Karrerby reacting with cyanogen chloride (ClCN) or cyanogen bromide oraccording to the method of J. Houben and W. Fisher, by reacting withe.g. trichloroacetonitrile. Advantageously, the standard catalystaluminum chloride is used in these reactions and hydrogen chloride orhydrogen bromide is released which can be removed from the reactionmixture after addition of a base, preferably an amine, for exampletriethylamine or pyridine.

The conversion of a compound of the formula XII wherein R₅ is halo, forexample, chloro, bromo or iodo, to a corresponding nitrile of theformula I is performed by using e.g. a cyanide salt, especially sodiumor potassium cyanide or, preferably, copper(I) cyanide. Preferredsolvents for this reaction are pyridine, quinoline, dimethylformamide,1-methyl-2-pyrrolidinone and hexamethylphosphoric triamide. Hightemperatures, especially reflux temperatures of the reaction mixture arepreferred.

The conversion of a compound of the formula XII wherein R₅ is asulfonyloxy group, for example p-toluenesulfonyloxy, benzenesulfonyloxyor mesyloxy, to a nitrile of the formula I is performed e.g. by reactionwith an alkali metal cyanide, preferably sodium or potassium cyanide.High temperatures, especially the reflux temperature of the reactionmixture, are preferred.

The conversion of a compound of the formula XII wherein R₅ is amino, toa nitrile of the formula I proceeds over several steps. First, adiazonium salt is formed e.g. by reaction of the amino compound with analkali metal nitrite preferably potassium nitrite. The diazonium saltcan be reacted using the well-known Sandmeyer reaction in situ e.g. withcuprous cyanide or a cyanide complex preferably potassium cuproammoniumcyanide, or with catalytic amounts of freshly precipitated copper powderin the presence of an alkali metal cyanide, for example sodium orpotassium cyanide.

The conversion of a compound of formula XII wherein R₅ is carboxy to anitrile of formula I can be carried out by reaction withchlorosulfonylisocyanate in e.g. dimethylformamide according to themethod of R. Graf, Angew. Chem. 80, 183 (1968).

The conversion of a compound of the formula XII wherein R₅ is a carboxygroup in the form of a functional derivative, for example carbamoyl,lower alkylcarbamoyl, advantageously t-butylcarbamoyl, to a nitrile ofthe formula I can be carried out e.g. with a strong dehydrating agent,such as phosphorus pentoxide, phosphoryl chloride, thionyl chloride,phosgene or oxalyl chloride. The dehydration can be preferably carriedout in the presence of a suitable base. A suitable base is, for example,an amine, for example a tertiary amine, for example tri-loweralkylamine, for example trimethylamine, triethylamine or ethyldiisopropylamine, or N,N-di-lower alkylaniline, for exampleN,N-dimethylaniline, or a cyclic tertiary amine, for example a N-loweralkylated morpholine, for example N-methylmorpholine, or is, forexample, a base of the pyridine type, for example pyridine or quinoline.

The conversion of a compound of formula XII wherein R₅ is formyl to anitrile of formula I is carried out e.g. by converting the formyl groupto a reactive functional derivative, for example a hydroxyiminomethylgroup, and converting this group to cyano by a dehydrating agent. Asuitable dehydrating agent is one of the inorganic dehydrating agentsmentioned above, for example phosphorous pentachloride, or, preferably,the anhydride of an organic acid, for example the anhydride of a loweralkane carboxylic acid, for example acetic acid anhydride. Theconversion of the formyl group to hydroxyiminomethyl is carried out byreacting a compound of formula IX wherein R₅ is formyl, e.g. with anacid addition salt of hydroxylamine, preferably the hydrochloride.

A compound of the formula XII wherein R₅ is formyl can also be converteddirectly to a corresponding nitrile of the formula I e.g. by reactionwith O,N-bis-(trifluoroacetyl)-hydroxylamine in the presence of a base,for example pyridine, according to the method of D. T. Mowry, Chem. Rev.42, 251 (1948).

The conversion of a compound of the formula XII wherein R₅ is ahalomagnesium group, for example, iodo-, bromo-, or chloromagnesium, toa corresponding nitrile of the formula I is performed e.g. by reactingthe magnesium halide with cyanogen halide or dicyanogen. The "Grignard"reagent, wherein R₅ is a halomagnesium group, is prepared in aconventional manner, for example by reacting a compound of the formulaXII wherein R₅ is halo, for example chloro, bromo or iodo, withmagnesium, e.g. in dry ether.

The compounds of the invention obtained by the above-cited processes canbe converted into other compounds of the invention of formula Iaccording to methodology known in the art and as illustrated herein.

Compounds of formula I, substituted by e.g. an acyloxy group, such aslower alkanoyloxy or aroyloxy, may be converted to compounds of formulaI substituted by hydroxy, by hydrolysis with e.g. aqueous acid such ashydrochloric acid, or with aqueous alkali, such as lithium or sodiumhydroxide.

conversely, the conversion of compounds of formula I substituted byhydroxy to compounds of formula I substituted by acyloxy, such asalkanoyloxy or aroyloxy, may be carried out by condensation with acorresponding carboxylic acid, or a reactive functional derivativethereof, according to acylation (esterification) procedures well-knownto the art.

The conversion of the compounds of formula I substituted by anetherified hydroxy group, e.g. lower alkoxy, to the compounds of formulaI substituted by a hydroxy group is carried out by methods well-known inthe art, e.g., with a mineral acid, such as hydriodic acid or,advantageously for compounds wherein lower alkoxy is methoxy, with e.g.boron triboromide in methylene chloride or with sodium or lithiumdiphenylphosphide in tetrahydrofuran.

The compounds of formula I wherein R₁ and R₂ represent hydrogen, i.e.the compounds of formula XI, may be converted to the compounds offormula I wherein R₁ and R₂ combined represent lower alkylidene, mono-or diaryl-lower alkylidene by reacting said compounds of formula XI withan appropriate aldehyde or ketone in the presence of a strong base, e.g.lithium diisopropylamide, and, if required, treating the resultingalcohols with a dehydrating agent, such as thionyl chloride.

Furthermore, the compounds of formula I wherein at least one of R₁ andR₂ represents hydrogen are converted to other compounds of formula I asdescribed above under process c).

Unless stated otherwise, the above reactions are preferably carried outin an inert, preferably anhydrous, solvent or solvent mixture, forexample in a carboxylic acid amide, for example a formamide, for exampledimethylformamide, a halogenated hydrocarbon, for example methylenechloride or chloroform, a ketone, for example acetone, a cyclic ether,for example tetrahydrofuran, an ester, for example ethyl acetate, or anitrile, for example acetonitrile, or in mixtures thereof, optionally atreduced or elevated temperature, for example in a temperature range fromapproximately -50° C. to approximately +150° C., preferably from roomtemperature to the boiling temperature of the reaction mixture andoptionally under inert gas atmosphere, for example nitrogen atmosphere,and at atmospheric pressure

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or theprocess is discontinued at any stage thereof, or in which the startingmaterials are formed under the reaction conditions or in which thereaction components are used in the form of their salts or opticallypure antipodes. Whenever desirable, the above processes are carried outafter first suitably protecting any potentially interfering reactivefunctional groups, as illustrated above and in the examples herein.

Advantageously, those starting materials should be used in saidreactions, that lead to the formation of those compounds indicated aboveas being preferred.

The invention also relates to novel starting materials and processes fortheir manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as pure geometric isomers (cis or trans), as pureoptical isomers (as antipodes), or as mixtures of optical isomers suchas racemates, or as mixtures of geometric isomers.

In case geometric or diastereomeric mixtures of the above compounds ofintermediates are obtained, these can be separated into the singleracemic or optically active isomers by methods in themselves known, e.g.by fractional distillation, crystallization and/or chromatography.

The racemic products or basic intermediates can be resolved into theoptical antipodes, for example, by separation of diastereomeric saltsthereof, e.g., by the fractional crystallization of d- or 1-(tartrate,dibenzoyltartrate, mandelate or camphorsulfonate) salts.

Any acidic intermediates or products can be resolved by separation ofe.g. the d- and 1-(alpha-methylbenzylamine, cinchonidine, cinchonine,quinine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts ofany compounds having an acidic salt-forming group.

Advantageously, the more active of the antipodes of the compounds ofthis invention is isolated.

Finally, the compounds of the invention are either obtained in the freeform, or as a salt thereof. Any resulting base can be converted into acorresponding acid addition salt, preferably with the use of apharmaceutically acceptable acid or anion exchange preparation, orresulting salt can be converted into the corresponding free bases, forexample, with the use of a stronger base, such as a metal or ammoniumhydroxide, or any basic salt, e.g., an alkali metal hydroxide orcarbonate, or a cation exchange preparation. These or other salts, forexample, the picrates, can also be used for purification of the basesobtained; the bases are converted into salts. In view of the closerelationship between the free compounds and the compounds in the form oftheir salts, whenever a compound is referred to in this context, acorresponding salt is also intended, provided such is possible orappropriate under the circumstances.

The compounds, including their salts, may also be obtained in the formof their hydrates, or include other solvents used for thecrystallization.

The present invention further relates to the use in mammals of thecompounds of formula I and II-VI and their pharmaceutically acceptableacid addition salts, or pharmaceutical compositions thereof, asmedicaments, particularly as aromatase inhibitors and as inhibitors ofestrogen biosynthesis, particularly for the treatment and ameliorationof estrogen dependent conditions, such as gynecomastia, mammary tumors,endometrial tumors, endometriosis and premature labor.

A particular embodiment of the invention thus relates to a method ofinhibiting aromatase activity and thereby suppressing estrogen synthesisin mammals by administering an effective aromatase inhibiting amount ofa compound of the invention, e.g. of formula I, or II, III, IV, V or VIor a pharmaceutically acceptable salt thereof, or of a pharmaceuticalcomposition comprising said compound, to a mammal in need thereof.

The present invention is thus also particularly directed to the methodof treatment in mammals of conditions responsive to aromataseinhibition, particularly estrogen dependent diseases, e.g. estrogendependent tumors such as mammary tumors, by administering an effectivearomatase inhibiting and estrogen biosynthesis inhibiting amount of acompound of the invention or of a pharmaceutical composition comprisingsuch compound, to a mammal in need thereof.

The present invention is further directed to a method of inhibitingfertility in female mammals (e.g. by inhibiting ovulation, inhibitingimplantation, inducing fetal resorption) which comprises administeringan effective amount of a compound of the invention or of apharmaceutical composition comprising such compound.

The present invention is further directed to a method of delayingproestrus and estrus and in inhibiting proestrus in the anestrus animal,especially in the canine, and can thus be used as birth control agentsin the female animal in need thereof, especially in the canine, byadministering to a female animal an effective amount of a compound ofthe present invention or a veterinarily acceptable salt thereof; or of aveterinary composition comprising said compound in combination with oneor more veterinarily acceptable carriers

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration.

A unit dosage for a mammal of about 50 to 70 kg may contain betweenabout 0.05 and 25 mg of an active ingredient.

The present invention also relates to the use of the compounds of theinvention for the preparation of pharmaceutical compositions, especiallypharmaceutical compositions having aromatase inhibiting or estrogenbiosynthesis inhibiting properties.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, for the treatment ofestrogen-dependent diseases responsive to aromatase inhibition,comprising an effective aromatase inhibiting amount of apharmacologically active compound of formula I, or II, III, IV, V or VIor a pharmacologically acceptable salt thereof, alone or in combinationwith one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients or carrierssuitable for either enteral or parenteral application. preferred aretablets and gelatin capsules comprising the Active ingredient togetherwith a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salts and/or polyethyleneglycol; fortablets also c) binders, e.g. magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluloseand/or polyvinylpyrrolidone; if desired, d) disintegrants, e.g.starches, agar, alginic acid or its sodium salt, or effervescentmixtures; and/or e) absorbents, colorants, flavors and sweeteners.Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, the compositions may also containother therapeutically valuable substances. Said compositions areprepared according to conventional mixing, granulating or coatingmethods, respectively, and contain preferably about 1 to 50% of theactive ingredient.

Suitable formulations for transdermal application include an effectiveamount of a compound of formula I, or II-VI with carrier. Advantageouscarriers include absorbable pharmaceutically acceptable solvents toassist passage through the skin of the host. Characteristically,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound, optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100 mmHg. The structure of final products, intermediates and startingmaterials is confirmed by analytical methods, e.g. microanalysis andspectroscopic characteristics (e.g. MS, IR, NMR).

EXAMPLE 1

a) A solution of alpha-bromo-4-tolunitrile (86.6 g) in dichloromethane(1000 mL) is mixed with imidazole (68.0 g). The mixture is stirred atambient temperature for 15 hours and then diluted with water (1000 mL).Any undissolved solid is removed by filtration and the separated organicsolution is then repeatedly washed with water (5×200 mL) to removeexcess imidazole, and then dried (MgSO₄). The crude product obtainedupon evaporation of the solvent can be purified by trituration with colddiethyl ether (200 mL) to obtain 4-(1-imidazolylmethyl)-benzonitrile,m.p. 99°-101°; HCl salt, m.p. 142°-144°.

Similarly prepared are:

b) 2-(1-imidazolylmethyl)-benzonitrile hydrochloride, m.p. 176°-177°;

c) 4-(1-imidazolylmethyl)-1-naphthonitrile hydrochloride, m.p. 210°-212°dec.;

EXAMPLE 2

a) A suspension of potassium tert-butoxide (61.6 g) in dimethylformamide(500 mL) is stirred and cooled to -10° (ice-salt bath), and a solutionof 4-(1-imidazolylmethyl)-benzonitrile (45.6 g) in dimethylformamide(250 mL) is added so that the reaction temperature remains below 0°. Theresulting solution is stirred at 0° for 0.5 hour and then a solution of4-fluorobenzonitrile (38.3 g) in dimethylformamide (100 mL) is addedwhile keeping reaction temperature below 5°. After 0.75 hour, thereaction mixture is neutralized to pH 7 by addition of sufficient 3Nhydrochloric acid and the bulk of the solvents are then removed underreduced pressure. The residue is diluted with water (500 mL) and thecrude product is extracted into ethyl acetate (3×200 mL). The combinedextracts are then extracted with 3N hydrochloric acid (3×150 mL) and,after washing the latter acid extracts with ethyl acetate (100 mL), thesolution is made basic (pH 8) with 6N ammonium hydroxide and the productis again extracted into ethyl acetate (3×150 mL). The combined extractsare dried (MgSO₄), decolorized by treatment with charcoal, and thenevaporated to give crude4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile as an oil.This material is dissolved in isopropanol (250 mL) and the warm solutionis stirred with succinic acid (14.4 g). Upon dilution with diethyl ether(100 mL) and stirring at ambient temperature, the hemi-succinate saltseparates. The salt is filtered off, washed with a little coldisopropanol and then air dried to afford4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile hemisuccinate,m.p. 149°-150°. The hemifumarate salt has m.p. 157°-158°.

Similarly prepared are:

b) 4-[alpha-(2-cyanophenyl)-1-imidazolylmethyl]benzonitrile, IR(CN) 2240cm⁻¹, M/e 384; HCl salt (hygroscopic), m.p. 90° (dec);

c) 4-[alpha-(4-trifluoromethylphenyl)-1-imidazolylmethyl]-benzonitrile,IR(CN) 2232 cm⁻¹, M/e 327; HCl salt (hygroscopic), m.p. 100° (dec).

EXAMPLE 3

a) A solution of 4-(alpha-chloro-4'-cyanobenzyl)benzonitrile (20.2 g)and imidazole (16.3 g) in dimethylformamide (130 mL) is stirred andheated at 160° for 2 hours. The reaction is cooled, diluted with water(800 mL) and extracted into ethyl acetate (3×150 mL). The remainder ofthe work-up is carried out in the manner described in Example 2 to yield4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile hemisuccinate,m.p. 148°-150°.

The starting material, 4-(alpha-chloro-4'-cyanobenzyl)-benzonitrile isprepared as follows:

A solution of N-tert-butyl-4-bromobenzamide (37.2 g) in anhydroustetrahydrofuran (1000 mL) is stirred under an atmosphere of N₂ andcooled to -60°. A solution of n-butyl lithium (125 mL, 2.4M in hexane,0.300 mole) is then added during 40 min and the resulting suspension isstirred for a further 40 min at -60°. A solution of ethyl formate (5.3g) in anhydrous tetrahydrofuran (50 mL) is then added dropwise during 10min and the reaction is allowed to proceed at -60° for 2 hours. Thereaction is then quenched by the addition of saturated aqueous ammoniumchloride (200 mL) and after allowing the mixture to reach roomtemperature, diethyl ether (300 mL) is added and the layers areseparated. The ethereal solution is washed with water (2×100 mL) andbrine (100 mL) and dried (MgSO₄). The solvent is evaporated and theresidue is triturated with diethyl ether (150 mL) to afford thebis(4-N-tert-butylcarbamoylphenyl)methanol, m.p. 200°-202°.

Bis-(4-N-tert-butylcarbamoylphenyl)methanol (17.6 g) is suspended inthionyl chloride (140 mL) and the mixture is stirred at reflux for 6hours. The solvent is evaporated and the residue is taken up in toluene(100 mL) and the solvent is evaporated. The latter procedure is repeatedonce more to afford the 4-(alpha-chloro-4'-cyanobenzyl)benzonitrile asan oil which is used directly; NMR(CH methine) 3.85 ppm.

EXAMPLE 4

Imidazole (9.4 g) and 4-(alpha-chloro-4'-cyanobenzyl)-benzonitrile (11.6g) are intimately mixed and heated together in an oil bath at 110°-120°for 15 hours. The reaction mixture is diluted with water (200 mL) andextracted with ethyl acetate (3×75 mL). The remainder of the work-up iscarried out as described in Example 2, yielding4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile. The crudeproduct is treated with an equivalent amount of fumaric acid in warmisopropanol to yield4-[alpha-(4-cyanophenyl)1-imidazolylmethyl]-benzonitrile hemifumarate,m.p. 156°-157°.

EXAMPLE 5

The following compounds are prepared according to the methods describedin previous examples 3 and 4 using the appropriate starting materials.

a) 2-[alpha-(4-bromophenyl)-1-imidazolylmethyl]benzonitrile, M/e 337;

b) 4-[alpha-(4-chlorophenyl)-1-imidazolylmethyl]benzonitrile; M/e=293;hydrochloride salt, m.p. 90° dec.

c) 4-[alpha-(4-methoxyphenyl)-1-imidazolylmethyl]benzonitrile, IR(CN)2235 cm⁻¹, M/e 289; hydrochloride salt(hygroscopic), m.p. 90° (dec);

d) 4-[alpha-(2-methoxyphenyl)-1-imidazolylmethyl]benzonitrile, IR(CN)2234 cm⁻¹, M/e 289; hydrochloride salt(hygroscopic), m.p. 95° (dec);

e) 4-[alpha-(3-pyridyl)-1-imidazolylmethyl]-benzonitrile, IR(CN) 2237cm⁻¹, M/e 260; dihydrochloride salt(hygroscopic), m.p. 150°; sulfatesalt, m.p. 238°-240°.

f) 4-[alpha-(2-thienyl)-1-imidazolylmethyl]-benzonitrile, IR(CN) 2237cm⁻¹ ; M/e 265; hydrochloride salt, m.p. 65° dec.

g) 4-[alpha-(3-thienyl)-1-imidazolylmethyl]-benzonitrile, IR(CN) 2240cm⁻¹, M/e 265; hydrochloride salt, m.p. 70° dec.

h) 4-(alpha-phenyl-1-imidazolylmethyl)-benzonitrile; M/e 259;hydrochloride salt, m.p. 90° dec. (hygroscopic);

i) 4-[alpha-(4-tolyl)-1-imidazolylmethyl]-benzonitrile; M/e 273;hydrochloride salt, m.p. 90° (dec), hygroscopic;

j) 3-(alpha-phenyl-1-imidazolylmethyl)-benzonitrile; M/e 259;hydrochloride salt(hygroscopic), m.p. 80° (dec);

The starting precursor for compound b is prepared as follows:

A solution of n-butyl lithium (20 mL of 2.4M reagent, 0.048 mole) inhexane is added dropwise under an atmosphere of N₂ to a solution ofN-tert-butyl-4-bromobenzamide (6.1 g, 0.024 mole) in tetrahydrofuran(100 mL) which is maintained at -60° and then a solution of4-chlorobenzaldehyde (5.1 g, 0.036 mole) in tetrahydrofuran (50 mL) isadded dropwise. The reaction is stirred for 2 h at -60° and thenquenched by the addition of saturated aqueous ammonium chloride (30 mL)and ether (100 mL). The ethereal layer is separated and washedrepeatedly (3×30 mL) with aqueous sodium bisulfite and finally withbrine and dried (MgSO₄). Solvent evaporation affords(4-chlorophenyl)-(4'-N-tert-butylcarbamoylphenyl)methanol as an oil,NMR(CH methine): 4.30 ppm, which can be used without furtherpurification.

The following carbinols are prepared in a similar manner using anappropriate starting material:

phenyl-(4'-N-tert-butylcarbamoylphenyl)methanol, NMR(CH methine) 4,27ppm;

(4-methoxyphenyl)-(4'-N-tert-butylcarbamoylphenyl)methanol, NMR(CHmethine) 4.23 ppm;

(2-methoxyphenyl)-(4'-N-tert-butylcarbamoylphenyl)methanol, NMR(CHmethine) 4.00 ppm;

(4-methylphenyl)-(4'-N-tert-butylcarbamoylphenyl)methanol, NMR(CHmethine) 4.23 ppm;

(3-pyridyl)-(4'-N-tert-butylcarbamoylphenyl)methanol, NMR(CH methine)4.20 ppm;

(2-thienyl)-(4'-N-tert-butylcarbamoylphenyl)methanol, NMR(CH methine)3.98 ppm;

(3-thienyl)-(4'-N-tert-butylcarbamoylphenyl)methanol, NMR(CH methine)4.05 ppm;

3-(alpha-hydroxybenzyl)-benzonitrile, NMR(CH methine) 4.20 ppm.

The appropriate starting cyanophenyl substituted chlorides correspondingto the above carbinols are prepared by treatment with thionyl chlorideas previously described in Example 3.

EXAMPLE 6

A solution of 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]benzonitrile(5.3 g) in dimethylformamide (20 mL) is added dropwise to a cooled(ice-bath) stirred suspension of potassium tert-butoxide (2.5 g) indimethylformamide (20 mL). This mixture is stirred for 30 min at 0°-5°and then a solution of methyl iodide (3.5 g) in dimethylformamide (10mL) is added during 10 min. After stirring at 0°-5° for a further 15min, the reaction is diluted with water (200 mL) and extracted withethyl acetate (3×60 mL). The organic solution is washed with water (50mL) and then extracted with 3N hydrochloric acid (3×30 mL). The extractsare made basic (pH 8) with aqueous sodium hydroxide and the product isagain extracted into ethyl acetate (2×50 mL). The extracts are dried(MgSO₄) and evaporated to give a solid which is recrystallized fromisopropanol to give 4-[alpha-(4-cyanophenyl)-alpha-methyl-1-imidazolylmethyl] benzonitrile, m.p. 184°-186°.

EXAMPLE 7

a) A solution of boron tribromide (11.7 g) in dichloromethane (50 mL) isadded dropwise during 30 min to a cooled (ice-bath) stirred solution of4-[alpha-(4-methoxyphenyl)-1-imidazolylmethyl]benzonitrile (3.2 g) indichloromethane (50 mL). The reaction is allowed to proceed at ambienttemperature for 15 hours and is then poured onto ice and water (100 mL).The pH is adjusted to 7 by the addition of solid sodium bicarbonate andthe layers are separated. The organic solution is washed with water,dried (MgSO₄) and evaporated. The residual crude product is trituratedwith diethyl ether to give4-[alpha-(4-hydroxyphenyl)-1-imidazolylmethyl]benzonitrile, m.p.196°-198°.

b) 4-[alpha-(2-hydroxyphenyl)-1-imidazolylmethyl]benzonitrile, m.p.230°-235° dec. is similarly prepared.

c) 4-[alpha-(4-hydroxybenzyl)-1-imidazolylmethyl]benzonitrile, m.p.238°-240° is also similarly prepared.

EXAMPLE 8

A solution containing2-[alpha-(4-bromophenyl)-1-imidazolylmethyl]benzonitrile (2.1 g) andhydrazine hydrate (10 mL) in 95% ethanol (60 mL) is mixed with 10% Pd-Ccatalyst (0.5 g) and the mixture is stirred at reflux for 21/2 hours.The catalyst is filtered off and the solvent evaporated to give an oilwhich is dissolved in 3N hydrochloric acid (20 mL). The acid solution isextracted with ethyl acetate (10 mL), neutralized to pH 7 with aqueoussodium hydroxide and extracted with ethyl acetate (3×10 mL). Theextracts are dried (MgSO₄) and evaporated to give the crude productwhich is further purified by flash column chromatography on silica gel.Elution with ethyl acetate affords2-[alpha-phenyl-1-imidazolylmethyl]benzonitrile; IR(CN): 2240 cm⁻¹ ; M/e259; hydrochloride salt, melting with dec.

EXAMPLE 9

A solution containing alpha-bromo-4-tolunitrile (19.6 g) and1,2,4-triazole (30.5 g) in a mixture of chloroform (250 mL) andacetonitrile (50 mL) is stirred at reflux for 15 hours. The solution iscooled and washed with 3% aqueous sodium bicarbonate (200 mL) and theorganic solution is then dried (MgSO₄) and evaporated. The residue ischromatographed on silica gel (300 g). Elution withchloroform/isopropanol (10:1) affords4-[1-(1,2,4-triazolyl)methyl]-benzonitrile, m.p. 77°-79°, which forms ahydrochloride salt, m.p. 200°-205°, when its solution in ethyl acetateis treated with ethereal HCl.

Further elution of the silica gel column with chloroform/isopropanol(3:2) affords 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile, m.p.151°-153°, which forms a hydrochloride salt, m.p. 236°-238°.

EXAMPLE 10

A solution containing alpha-bromo-4-tolunitrile (11.0 g),1-(dimethylcarbamoyl)-4-methylimidazole (8.6 g) and sodium iodide (8.4g) in acetonitrile (75 mL) is heated and stirred at reflux for 15 hours.The mixture is cooled to 0° (ice-bath) and ammonia gas is bubbledthrough the solution for 15 minutes. The volatiles are then evaporatedand the residue is partitioned between water (150 mL) and ethyl acetate(150 mL). The organic solution is washed with water (2×50 mL) and isthen extracted with 3N hydrochloric acid. The combined acidic extractsare made basic (pH 9) with 6N sodium hydroxide and the product isextracted into ethyl acetate (3×60 mL). After drying (MgSO₄), solventevaporation affords crude 4-[1-(5-methylimidazolyl)methyl]-benzonitrilewhich forms a hydrochloride salt, m.p. 203°-205°, when its solution inacetone is treated with ethereal HCl.

The starting material is prepared in the following manner:

A solution containing 4-methylimidazole (16.4 g), N,N-dimethylcarbamoylchloride (30 g) and triethylamine (30 g) in acetonitrile (125 mL) isstirred at reflux for 20 hours. Upon cooling, the reaction is dilutedwith diethyl ether (1000 mL) and then filtered. The filtrate isconcentrated and the residue is distilled under reduced pressure.1-(Dimethylcarbamoyl)-4-methylimidazole is obtained as a colorlessliquid, b.p. 104°-106° at 0.35 mm Hg.

EXAMPLE 11

a) A solution of n-butyl lithium (25 mL of 2.1M reagent in hexane,0.0525 mole) is added dropwise in an N₂ atmosphere to a solution ofdi-isopropylamine (5.6 g) in tetrahydrofuran (100 mL) which ismaintained at -20°. This cold solution is then added dropwise to asolution of 4-(1-imidazolylmethyl)benzonitrile (9.15 g) intetrahydrofuran (250 mL) which is maintained at -50° during addition andfor 30 minutes subsequently. The reaction mixture is then cooled to -70°and methyl iodide (10.7 g) is added, all at once. The reaction isstirred at -70° for 30 minutes and then without external cooling for 10hours. The reaction is quenched by addition of water (300 mL) andextracted with diethyl ether (3×100 mL). The combined ether extracts areextracted with 3N hydrochloric acid (3×60 mL) and the acid extracts aremade basic (pH 9) with 6N sodium hydroxide. The crude product isextracted into ether (3×60 mL), and after drying (MgSO₄) and solventevaporation, 4-[1-(1-imidazolyl)ethyl]benzonitrile is obtained. Thecrude material is dissolved in acetone and treated with ethereal HCl toafford the hydrochloride salt, m.p. 184°-186°.

Similarly prepared are:

b) 4-[2-(1-imidazolyl)propyl]benzonitrile hydrochloride, m.p. 219°-221°;

c) 4-(alpha-n-butyl-1-imidazolylmethyl)-benzonitrile oxalate, m.p.73°-75°;

d) 4-(alpha-isopropyl-1-imidazolylmethyl)-benzonitrile, m.p. 94°-95°;

e) 4-(alpha-benzyl-1-imidazolylmethyl)benzonitrile hydrochloride, m.p.221°-223°;

f) 4-[alpha-(4-cyanobenzyl)-1-imidazolylmethyl]benzonitrile, m.p.199°-201°.

EXAMPLE 12

The lithium salt of 10.0 g of 4-(1-imidazolylmethyl)benzonitrile isprepared in THF (250 mL) in the manner described in Example 11. Thissolution is cooled to -60° and solid paraformaldehyde (10.0 g,previously dried for 15 hours in vacuo at 60° ) is added, all at once.The reaction mixture is stirred at -60° for 1 hour and then withoutcooling for a further 15 hours. The reaction is then quenched with water(200 mL) and worked up in the manner described in Example 11 to afford amixture of 4-(alpha-hydroxymethyl-1-imidazolylmethyl)benzonitrile and4-(alpha-methylene-1-imidazolylmethyl)benzonitrile which ischromatographed on silica gel (250 g). Elution with a mixture ofmethylene chloride and isopropanol (19:1) affords4-(alpha-methylene-1-imidazolylmethyl)benzonitrile. This compound formsa hydrochloride salt, m.p. 195°-197° when its solution in acetone istreated with ethereal HCl.

EXAMPLE 13

a) Racemic 4-[1-(1-imidazolyl)ethyl]benzonitrile (3.5 g) is dissolved inwarm acetone (50 mL) and added to a solution of 1-tartaric acid (1.2 g)in warm acetone (300 mL). The mixture is allowed to stand at roomtemperature overnight and the tartrate salt is collected. This materialis recrystallized four times from minimal volumes of anhydrous ethanoland the resultant material is converted to the free base by dissolutionin water, making basic (pH 9) with dilute sodium hydroxide and isolating(-)-4-[1-(1-imidazolyl)ethyl]benzonitrile which has an optical rotation[alpha]D²⁵ =-4.94°.

b) (+)-4-[1-(1-Imidazolyl)ethyl]benzonitrile is obtained in a similarmanner using d-tartaric acid and has an optical rotation [alpha]D²⁵=+4.89°.

Each enantiomer forms a hydrochloride salt, m.p. 190°-191°, when asolution in acetone is treated with ethereal HCl.

EXAMPLE 14

A solution of potassium tert-butoxide (1.10 g) in tetrahydrofuran (50mL) is added dropwise to a solution of4-[1-(1-imidazolyl)-5-chloropentyl]benzonitrile (2.50 g) intetrahydrofuran at 0° (ice-bath). The reaction is allowed to proceed at0° for 30 minutes and is then allowed to warm to room temperature during3 hours. The reaction is then quenched with water (100 mL) and themixture is subsequently extracted with ethyl acetate (100 mL). Theorganic extract is extracted with 3N hydrochloric acid (3×30 mL) and thecombined acid extracts are made basic with 6N sodium hydroxide. Thecrude product is extracted into ethyl acetate (3×30 mL) and the combinedextracts are dried (MgSO₄) and evaporated to afford1-(4-cyanophenyl)-1-(1-imidazolyl)cyclopentane as an oil. The compoundis dissolved in acetone and treated with ethereal HCl to afford thehydrochloride salt, m.p. 217°-219°.

The starting material, 4-[1-(1-imidazolyl)-5-chloropentyl]benzonitrileis prepared as follows:

The lithium salt of 4-[1-imidazolylmethyl]-benzonitrile (3.7 g) isprepared at -50° in tetrahydrofuran (100 mL) as described in Example 11,and the cold solution is then added dropwise to a solution of1-chloro-4-iodobutane (8.7 g) in tetrahydrofuran (60 mL) at -60°. Thereaction is maintained at -60° for 2 hours and is then quenched byaddition of water (150 mL). The product is extracted as described inExample 11 and the chloropentyl intermediate is obtained as an oil. Themethine-CH (triplet) is observed at 4.77 ppm in the NMR spectrum. Thematerial is used without further purification.

EXAMPLE 15

A solution of potassium tert-butoxide (4.5 g) in tetrahydrofuran (125mL) is added dropwise during 1 hour to a solution of4-[1-imidazolylmethyl]benzonitrile (3.66 g) andalpha,alpha'-dichloro-o-xylene (3.50 g) in tetrahydrofuran (100 mL)which is maintained at 0° (ice-bath). The reaction mixture issubsequently stirred for a further 1 hour without external cooling andis then quenched with water (200 mL) and extracted with ethyl acetate(150 mL). The organic extracts are then extracted with 3N hydrochloricacid (3×80 mL) and the acidic extracts are made basic with 6N sodiumhydroxide and the crude product is extracted into ethyl acetate (3×50mL). The material obtained after drying (MgSO₄) and solvent evaporationis chromatographed on silica gel (100 g). Elution with ethyl acetateaffords the crystalline 2-(4-cyanophenyl)-2-(1-imidazolyl)indane whichis recrystallized from isopropanol, m.p. 150°-152°.

EXAMPLE 16

a) The lithium salt of 4-[1-imidazolylmethyl]benzonitrile (3.7 g) isprepared at -50° in tetrahydrofuran (100 mL) in the manner described inExample 11. This cold solution is then added dropwise to a solution ofdiphenyl disulfide (6.5 g) in tetrahydrofuran (100 mL) at -50°. Thereaction mixture is stirred for 2 hours, then quenched by addition ofwater (150 mL) and worked up as described in Example 11 to afford4-[alpha-phenylthio-1-imidazolylmethyl]benzonitrile as an oil. Thecompound forms a hydrochloride salt, m.p. 159°-162°, when its solutionin ether is treated with ethereal HCl.

b) 4-[alpha-Methylthio-1-imidazolylmethyl]benzonitrile hydrochloride,m.p. 137°-140°, is similarly prepared.

EXAMPLE 17

2,2-Bis-(4-methoxyphenyl)-2-hydroxy-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethane(10.2 g) is dissolved in thionyl chloride (25 mL) and the solution isstirred at room temperature for 36 hours. The solvent is evaporated andthe residue is chromatographed on silica gel (250 g). Elution with ethylacetate affords the crystalline2,2-bis-(4-methoxyphenyl)-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethylene.The compound has m.p. 174°-176° after recrystallization fromisopropanol.

The starting material is prepared as follows:

The lithium salt of 4-(1-imidazolylmethyl)benzo nitrile (5.5 g) isprepared in tetrahydrofuran (200 mL) in the manner described in Example11. This cold solution is added dropwise to a solution of4,4'-dimethoxybenzophenone (7.5 g) in tetrahydrofuran (100 mL) at -60°.The reaction is allowed to proceed for 4 hours at -60° and is thenquenched by dropwise addition of acetic acid (0.5 mL) and then water(200 mL). After warming to room temperature, the mixture is diluted withether (200 mL). The separated organic phase is washed with water (3×50mL), dried over MgSO₄ and, after evaporating the solvents, the residueis chromatographed on silica gel (200 g). Elution with ethyl acetateaffords2,2-bis-(4-methoxyphenyl)-2-hydroxy-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethaneas a foam (NMR, CH-methine 4.15 ppm).

EXAMPLE 18

Treatment of2,2-bis-(4-methoxyphenyl)-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethylenewith boron tribromide using procedure analogous to that described inExample 7 yields2,2-bis-(4-hydroxyphenyl)-1-(1-imidazolyl)-1-(4-cyanophenyl)-ethylenehydrobromide, m.p. 178° dec.

EXAMPLE 19

a) Zinc dust (23 g) is added in small portions over 15 minutes to asolution of 4-(alpha-chloro-3-pyridylmethyl)benzonitrile hydrochloride(13.25 g) in a mixture of acetic acid (110 mL) and water (5 mL). Thereaction is stirred at room temperature for 3 hours and is then filteredthrough a pad of Celite. The filtrate is concentrated and the residue istaken up in ether (250 mL) and washed with 3N sodium hydroxide (3×100mL) and brine. After drying the ethereal solution (anhydrous Na₂ SO₄),solvent evaporation affords crude 4-(3-pyridylmethyl)-benzonitrile. Thecompound forms a hydrochloride salt, m.p. 155°-157°, when its solutionin ethyl acetate is treated with ethereal HCl.

The starting material is prepared from(3-pyridyl)(4'-N-tert-butylcarbamoylphenyl)-methanol by treatment withthionyl chloride as described in Example 3.

(3-Pyridyl)-(4'-N-tert-butylcarbamoylphenyl)-methanol is prepared fromN-tert-butyl-4-bromobenzamide and 3-pyridinecarboxaldehyde (see Example3).

Similarly prepared are:

b) 4-[alpha-(3-pyridyl)-3'-pyridylmethyl]benzonitrile, m.p. 125°-127°;

c) 4-[alpha-(4-pyridyl)-3'-pyridylmethyl]benzonitrile oxalate, m.p.172°-174°.

EXAMPLE 20

a) 4-[1-(1,2,4-Triazolyl)-methyl]-benzonitrile is reacted with potassiumtert-butoxide and 4-fluorobenzonitrile according to procedure in Example2 to yield4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile, m.p.181°-183°.

b) 4-[1-(1,3,4-Triazolyl)-methyl]-benzonitrile is similarly reacted with4-fluorobenzonitrile to yield4-[alpha-(4-cyanophenyl)-1-(1,3,4-triazolyl)-methyl]benzonitrile, m.p.239°-243°.

EXAMPLE 21

4-(3-Pyridylmethyl)-benzonitrile is reacted with potassium tert-butoxideand 4-fluorobenzonitrile according to the procedure in Example 2 toyield 4-[alpha-(4-cyanophenyl)-3-pyridylmethyl]-benzonitrilehydrochloride, m.p. 120°-125° dec.

EXAMPLE 22

To 48.0 L of acetone under nitrogen is added 4.326 Kg of potassiumcarbonate, 0.26 Kg of potassium iodide, 3.2 Kg of imidazole and 4.745 Kgof alpha-chloro-4-tolunitrile. The mixture is stirred at 45° undernitrogen for 26 hours. The reaction is cooled, filtered and the solventis evaporated at reduced pressure. The residue is redissolved in 40 L ofmethylene chloride, washed with 40 L of water and twice with 10 L ofwater. The organic phase is dried over magnesium sulfate and evaporatedto yield the crude product which is stirred with 6.4 L of ether for 2hours. The solid is filtered, washed with 9 L of ether and dried at 40°and 20 mm Hg for 17 hours to yield 4-(1-imidazolylmethyl)-benzonitrile,the compound of Example 1.

EXAMPLE 23

In portions of approximately 500 g, 4.44 Kg of potassium tert-butoxideis added to 25 L of dimethylformamide, precooled to -10°, withoutallowing the solvent temperature to rise above -4°. The solution isrecooled to -8° and a solution of 3.3 Kg4-(1-imidazolylmethyl)-benzonitrile in 12.5 L of dimethylformamide isadded within 3.3 hours. The rate of addition is adjusted to maintain thereaction temperature at -7±2°.

The solution is stirred for 45 minutes while cooling to -11 ° and asolution of 2.18 Kg of para-fluorobenzonitrile in 5 L ofdimethylformamide is added over 3.5 hours. The reaction temperature ismaintained at 3±4°. After 1.25 hours, the pH of the reaction is broughtto 7 with 3.0 L of concentrated hydrochloric acid, stirred an additional20 minutes and allowed to stand overnight. The solvent is removed bydistillation at 8 mm Hg over 7 hours. The resulting oil is partitionedbetween 25 L of methylene chloride and 35 L of water. The layers areseparated. The aqueous phase is extracted with 7 L of methylene chlorideand the combined organic phases are washed with 10 L of H₂ O and twicewith 1.1 L of 3N hydrochloric acid. The combined acidic layers arewashed with 7 L of methylene chloride and added to a mixture of 10 Kg ofice and 20 L of methylene chloride. The solution is stirred and broughtto pH 11 with 2.8 L of concentrated sodium hydroxide. The aqueous layeris separated and extracted with 5 L of methylene chloride. The combinedorganic phases are washed with 10 L of water and dried over magnesiumsulfate. Filtration and evaporation at 45° and 8 mm Hg, yields4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile as an oil; IR(CH₂ Cl₂)2240 cm⁻¹.

A solution of 9.23 Kg of the above free base in 19.1 L of isopropanol istreated with 0.45 Kg of decolorizing carbon and after 15 minutes isfiltered into a stirred solution of 1.84 Kg of succinic acid in 31.4 Lof isopropanol at 50°. The solution is stirred for 14 hours at 50° andallowed to cool to room temperature. The resulting crystalline solid iscollected by filtration, washed with 8 L of isopropanol and 5 L ofdiethyl ether and dried at 90° and 20 mm Hg for 28 hours to yield4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]benzonitrile hemisuccinate,m.p. 149°-150°. Recrystallization from isopropanol/ether gives productmelting at 151°-152°.

EXAMPLE 24

To a solution of 39.2 g of alpha-bromo-p-tolunitrile in 1 L of acetoneare added sequentially 20.72 g of 1,2,4-triazole, 27.8 g of potassiumcarbonate and 1.7 g of potassium iodide. The reaction is stirred for 8hours at 55° under argon, cooled to room temperature, filtered andevaporated. The residue is partitioned between methylene chloride andwater. The organic phase is separated, washed with brine, dried oversodium sulfate and evaporated. The resulting crystalline crude productis chromatographed on 300 g of silica with toluene and ethyl acetate(1:1 to 0:1) to yield 4-[1-(1,2,4-triazolyl)methyl]benzonitrile (seeexample 9).

EXAMPLE 25

(a) To a stirring solution of potassium tert-butoxide (4.8 g) in 40 mLof dimethylformamide is added dropwise a solution of4-[1-(1,2,4-triazolyl)methyl]benzonitrile (3.7 g) in 40 mL ofdimethylformamide. The mixture is stirred for 30 minutes and a solutionof 4-fluorobenzonitrile (2.7 g) in 20 mL of dimethylformamide is addeddropwise. After 30 minutes, the reaction is quenched with saturatedaqueous ammonium chloride and the mixture is evaporated to dryness. Theresidue is diluted with water and extracted three times with ethylacetate. The combined extracts are washed twice with water, and oncewith saturated brine solution. The ethyl acetate extract is dried overmagnesium sulfate and evaporated to dryness. The residue is trituratedwith ether and then recrystallized from 95% ethanol to yield4-[alpha(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]-benzonitrile, m.p.181°-183°.

(b) Using 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile as startingmaterial in the above procedure,4-[alpha-(4-cyanophenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile, m.p.239°-243°, is obtained.

EXAMPLE 26

A solution of 46 g of 4-[1-(1,2,4-triazolyl)-methyl]benzonitrile in 350ml of dimethylformamide is slowly added with external cooling to 77 g ofpotassium tert-butoxide in 250 ml of dimethylformamide, so that thetemperature stays between 24° and 26°. After 45 minutes, a solution of37.75 g of 4-fluorobenzonitrile in 250 mL of dimethylformamide is added.The reaction mixture is stirred an additional 30 minutes at roomtemperature, diluted with 100 mL of methylene chloride, cooled to 0°,brought to pH 7.3 with concentrated HCl and evaporated. The residue ispartitioned between methylene chloride and water. The organic phase isseparated, washed with brine dried over sodium sulfate and evaporated.The resulting crude product is recrystallized from ether/ethyl acetateto yield4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile, m.p.184°-185°.

EXAMPLE 27

The following compounds are prepared according to methodology describedin Examples 25 and 26.

(a) 4-[1-(1,2,4-triazolyl)-methyl]-benzonitrile is reacted with4-bromofluorobenzene to yield4-[alpha-(4-bromophenyl)-1-(1,2,4-triazolyl)-methyl]-benzonitrile.

(b) 4-1-(1,3,4-triazolyl)-methyl]-benzonitrile is reacted with2-fluorobenzonitrile to yield4-[alpha-(2-cyanophenyl)-1-(1,3,4-triazolyl)-methyl]-benzonitrile.

(c) 4-[1-(1,2,4-triazolyl)-methyl]-benzonitrile is reacted with4-(trifluoromethyl)-fluorobenzene to yield4-[alpha-(4-trifluoromethylphenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile.

EXAMPLE 28

1,2,4-Triazole (9.5 g) and 4-(alpha-chloro-4'-cyanobenzyl)-benzonitrile(11.6 g) are intimately mixed and heated together in an oil bath at110°-120° for 15 hours. The reaction mixture is diluted with water (200mL) and extracted with ethyl acetate (3×75 mL). The remainder of thework-up is carried out as described in Example 9, yielding4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile, and4-[alpha-(4-cyanophenyl)1-(1,3,4-triazolyl)-methyl]benzonitrile.

EXAMPLE 29

A solution of 4-(alpha-chloro-4'-cyanobenzyl)-benzonitrile (20.2 g) and1,2,4-triazole (16.5 g) in dimethylformamide (130 mL) is stirred andheated at 160° for 2 hours. The reaction is cooled, diluted with water(800 mL) and extracted into ethyl acetate (3×150 mL) The remainder ofthe work-up is carried out in the manner described in Example 9 to yield4-[alpha-(4-cyanophenyl)1-(1,2,4-triazolyl)methyl]-benzonitrile and4-[alpha(4-cyanophenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

The starting material, 4-(alpha-chloro-4'-cyanobenzyl)-benzonitrile isprepared as described in Example 3.

EXAMPLE 30

The following compounds are prepared according to the methods describedin examples 28 and 29.

(a) 1,2,4-Triazole is reacted with4-(alpha-chloro-4'-bromobenzyl)benzonitrile to yield4-[alpha-(4-bromophenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha-(4-bromophenyl)-1-(1,3,4-triazolyl)methyl]-benzonitrile.

(b) 1,2,4-Triazole is reacted with2-(alpha-chloro-4'-chlorobenzyl)benzonitrile to yield2-[alpha-(4-chlorophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile and2-[alpha-(4-chlorophenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(c) 1,2,4-Triazole is reacted with4-(alpha-chloro4'-bromobenzyl)benzonitrile to yield2-[alpha-(4-bromophenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile and2-[alpha-(4-bromophenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(d) 1,2,4-Triazole is reacted with4-(alpha-chloro4'-methoxybenzyl)benzonitrile to yield4-[alpha(4-methoxyphenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha-(4-methoxyphenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(e) 1,2,4-Triazole is reacted with 4-(alpha-chloro-benzyl)benzonitrileto yield4-[alpha-(2-methoxyphenyl-1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha-(2-methoxyphenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(f) 1,2,4-Triazole is reacted with4-[alpha-chloro-(3'-pyridyl)methyl]benzonitrile to yield4-[alpha-(3-pyridyl)-1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha-(3-pyridyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(g) 1,2,4-Triazole is reacted with4-[alpha-chloro-(2-thienyl)methyl]benzonitrile to yield4-[alpha-(2-thienyl)-1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha-(2-thienyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(h) 1,2,4-Triazole is reacted with4-[alpha-chloro-(3-thienyl)methyl]benzonitrile to yield4-[alpha-(3-thienyl)-1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha-(3-thienyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(i) 1,2,4-Triazole is reacted with 4-(alpha-chlorobenzyl)benzonitrile toyield 4-[alpha-phenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha-phenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(j) 1,2,4-Triazole is reacted with4-[alpha-chloro(p-tolyl)methyl]benzonitrile to yield4-[alpha-(p-tolyl)1-(1,2,4-triazolyl)methyl]benzonitrile and4-[alpha(p-tolyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

(k) 1,2,4-Triazole is reacted with 3-(alpha-chlorobenzyl)benzonitrile toyield 3-[(alpha-phenyl)1-(1,2,4-triazolyl)methyl]benzonitrile and3-[(alphaphenyl)-1-(1,3,4-triazolyl)methyl]benzonitrile.

The starting alpha-chloro compounds are prepared as generally describedin Examples 3 and 5.

EXAMPLE 31

(a) Using procedure essentially as described in Example 6,4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile istreated with methyl iodide to obtain4-[alpha-(4-cyanophenyl)-alpha-methyl1-(1,2,4-triazolyl)methyl]benzonitrile.

(b)4-[alpha-(4-cyanophenyl)-alpha-methyl-1-(1,3,4-triazolyl)methyl]benzonitrileis similarly prepared.

EXAMPLE 32

(a) Using procedure in Example 7,4-[alpha(4-methoxyphenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile isconverted to 4-[alpha-(4-hydroxyphenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile.

(b) 4-[alpha-(2-hydroxyphenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile issimilarly prepared.

(c) 4-[alpha-(4-hydroxybenzyl)-1-(1,2,4-triazolyl)methyl]benzonitrile,is also similarly prepared.

EXAMPLE 33

Using procedure described in Example 8,2-[alphaphenyl-1-(1,2,4-triazolyl)methyl]-benzonitrile is prepared from2-[alpha-(4-bromophenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile. 1Example 34

(a) A solution of n-butyl lithium (25 mL of 2.1M reagent in hexane,0.0525 mole) is added dropwise in an N₂ atmosphere to a solution ofdi-isopropylamine (5.6 g) in tetrahydrofuran (100 mL) which ismaintained at -20°. This cold solution is then added dropwise to asolution of 4-[1-(1,2,4-triazolylmethyl)benzonitrile (9.10 g) intetrahydrofuran (250 mL) which is maintained at -50° during addition andfor 30 minutes subsequently. The reaction mixture is then cooled to -70°and 7.1 g (3.1 mL) of methyl iodide is added dropwise. The reaction isstirred at -70° for 30 minutes and then without external cooling for 10hours. The reaction is quenched by addition of water (300 mL) andextracted with diethyl ether (3×100 mL). The combined ether extracts areextracted with 3N hydrochloric acid (3×60 mL) and the acid extracts aremade basic (pH 9) with 6N sodium hydroxide. The crude product isextracted into ether (3×60 mL), and after drying (MgSO₄) and solventevaporation, 4-[1-(1-(1,2,4-triazolyl)ethyl]benzonitrile is obtained.

The following compounds are similarly prepared as follows:

(b) 4-[1-(1-(1,2,4-triazolyl))ethyl]benzonitrile (9.35 g) is reactedwith 7.1 g of methyl iodide to yield4-[alpha,alpha-dimethyl-(1-(1,2,4-triazolyl))-methyl]benzonitrile.

(c) 4-[1-(1-(1,2,4-triazolyl))methyl]benzonitrile (9.10 g) is reactedwith 8.5 g of 2-iodopropane to yield4-[alpha-isopropyl-1-(1,2,4-triazolyl)methyl]benzonitrile.

(d) 4-[1-(1-(1,2,4-triazolyl))methyl]benzonitrile (9.10 g) is reactedwith 8.55 g of benzyl bromide to yield4-[alpha-benzyl-1-(1,2,4-triazolyl)methyl]benzonitrile.

(e) 4-[1-(1-(1,2,4-triazolyl))methyl]benzonitrile (9.10 g) is reactedwith 6.85 g of n-butyl bromide to yield4-[alpha-n-butyl-1-(1,2,4-triazolyl)methyl]benzonitrile.

(f) 4-[1-(1-(1,2,4-triazolyl))methyl]benzonitrile (9.10 g) is reactedwith 9.7 g of alpha-bromo-p-tolunitrile to yield4-[alpha-(4-cyanobenzyl-1-(1,2,4-triazolyl)methyl]benzonitrile.

EXAMPLE 35

The lithium salt of 10.0 g of 4-(1-(1,2,4-triazolyl)methyl)-benzonitrileis prepared in THF (250 mL) in the manner described in Example 34. Thissolution is cooled to -60° and solid paraformaldehyde (10.0 g,previously dried for 15 hours in vacuo at 60° ) is added, all at once.The reaction mixture is stirred at -60° for 1 hour and then withoutcooling for a further 15 hours. The reaction is then quenched with water(200 mL) and worked up in the manner described in Example 34 to afford amixture of 4-(alpha-hydroxymethyl-1-(1,2,4-triazolyl)methyl)benzonitrileand 4-(alpha-methylene-1-(1,2,4-triazolyl)-methyl)benzonitrile which ischromatographed on silica gel to afford4-(alpha-methylene-1-(1,2,4-triazolyl)-methyl)benzonitrile.

EXAMPLE 36

A solution of potassium tert-butoxide (1.10 g) in tetrahydrofuran (50mL) is added dropwise to a solution of4-[1-(1,2,4-triazolyl)-5-chloropentyl]benzonitrile (2.50 g) intetrahydrofuran at 0° (ice-bath). The reaction is allowed to proceed at0° for 30 minutes and is then allowed to warm to room temperature during3 hours. The reaction is then quenched with water (100 mL) and themixture is subsequently extracted with ethyl acetate (100 mL). Theorganic extract is extracted with 3N hydrochloric acid (3×30 mL) and thecombined acid extracts are made basic with 6N sodium hydroxide. Thecrude product is extracted into ethyl acetate (3×30 mL) and the combinedextracts are dried (MgSO₄) and evaporated to afford1-(4-cyanophenyl)-1-(1,2,4-triazolyl)cyclopentane. The compound isdissolved in acetone and treated with ethereal HCl to afford thehydrochloride salt.

The starting material,4-[1-(1,2,4-triazolyl)-5-chloropentyl]benzonitrile is prepared asfollows:

The lithium salt derived from 3.7 g of4-[1,2,4-triazolylmethyl]-benzonitrile is prepared as described inExample 34, and the cold solution is then added dropwise to a solutionof 1-chloro-4-iodobutane (8.7 g) in tetrahydrofuran (60 mL) at 60°. Thereaction is maintained at -60° for 2 hours and is then quenched byaddition of water (150 mL). The product is isolated by extraction andused without further purification.

EXAMPLE 37

A solution of potassium tert-butoxide (4.5 g) in tetrahydrofuran (125mL) is added dropwise during 1 hour to a solution of4-[1-(1,2,4-triazolyl)-methyl]benzonitrile (3.68 g) andalpha,alpha'-dichloro-o-xylene (3.50 g) in tetrahydrofuran (100 mL)which is maintained at 0° (ice-bath). The reaction mixture issubsequently stirred for a further 1 hour without external cooling andis then quenched with water (200 mL) and extracted ith ethyl acetate(150 mL). The organic extracts are then extracted with 3N hydrochloricacid (3×80 mL) and the acidic extracts are made basic with 6N sodiumhydroxide and the crude product is extracted into ethyl acetate (3×50mL). The material obtained after drying (MgSO₄) and solvent evaporationis chromatographed on silica gel (100 g). Elution with ethyl acetateaffords 2-(4-cyanophenyl)-2-[1-(1,2,4-triazolyl)]indane.

EXAMPLE 38

(a) The lithium salt of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile (3.7g) is prepared at -50° in tetrahydrofuran (100 mL) in the mannerdescribed in Example 34. This cold solution is then added dropwise to asolution of diphenyl disulfide (6.5 g) in tetrahydrofuran (100 mL) at-50°. The reaction mixture is stirred for 2 hours, then quenched byaddition of water (150 mL) and worked up as described in Example 34 toafford 4-[alphaphenylthio-1-(1,2,4-triazolyl)methyl]-benzonitrile.

(b) 4-[alpha-Methylthio-1-(1,2,4-triazolyl)methyl]benzonitrile issimilarly prepared.

EXAMPLE 39

Racemic 4-[1-(1,2,4-triazolyl)-ethyl]benzonitrile is treated essentiallyas described in Example 13 with 1-tartaric acid or d-tartaric acid toobtain the optical antipodes(-)4-[1-(1,2,4-triazolyl)-ethyl]benzonitrile and(+)4-[1-(1,2,4-triazolyl)-ethyl]benzonitrile.

EXAMPLE 40

The following compounds are prepared according to methodology describedin the previous examples.

(a) 4-(3-pyridylmethyl)-benzonitrile is reacted with4-bromofluorobenzene to yield4-[alpha-(4-bromophenyl)-3-pyridylmethyl]-benzonitrile.

(b) 4-(3-pyridylmethyl)-benzonitrile is reacted with2-fluorobenzonitrile to yield4-[alpha-(2-cyanophenyl)-3-pyridylmethyl]-benzonitrile.

(c) 4-[3-pyridylmethyl]-benzonitrile is reacted with4-(trifluoromethyl)-fluorobenzene to yield4-[alpha-(4-trifluoromethylphenyl)-3-pyridylmethyl]benzonitrile.

EXAMPLE 41

(a) Using methodology described e.g. in example 34,4-(3-pyridylmethyl)-benzonitrile is reacted with methyl iodide to obtain4-[1-(3-pyridyl)-ethyl]-benzonitrile.

(b) Similarly 4-[1-(3-pyridyl)-ethyl]-benzonitrile is again reacted withmethyl iodide to obtain4-(alpha,alphadimethyl-3-pyridylmethyl)-benzonitrile.

(c) Similarly 4-(3-pyridylmethyl)-benzonitrile is reacted withalpha-bromo-p-tolunitrile to yield4-[alpha-(4-cyanobenzyl)-3-pyridylmethyl]-benzonitrile.

EXAMPLE 42

Using procedure as described in the previous examples,4-[alpha-(4-cyanophenyl)-3-pyridylmethyl]benzonitrile is reacted withmethyl iodide to obtain4-[alpha(4-cyanophenyl)-alpha-methyl-3-pyridylmethyl]benzonitrile.

EXAMPLE 43

Using procedure described in Example 36, the lithium salt of4-(3-pyridylmethyl)-benzonitrile is treated with 1-chloro-4-iodobutaneand the intermediate cyclized to obtain1-(4-cyanophenyl)-1-(3-pyridyl)-cyclopentane.

EXAMPLE 44

A suspension of potassium tert-butoxide (2.0 g) in dimethylformamide (15mL) is stirred and cooled to -10° (ice-salt bath), and a solution of4-(3-pyridylmethyl)benzonitrile (1.55 g) in dimethylformamide (10 mL) isadded so that the reaction temperature remains below 0°. The resultingsolution is stirred at 0° for 0.5 hour and then a solution of4-fluorobenzonitrile (1.1 g) in dimethylformamide (10 mL) is added whilekeeping reaction temperature below 5°. The reaction mixture is stirredat room temperature overnight, treated with saturated aqueous ammoniumchloride and evaporated to dryness. The residue is diluted with waterand the crude product is extracted 3 times with 3N hydrochloric acidand, after washing the acid extracts with ether, the solution is madebasic with dilute sodium hydroxide and the product is again extractedinto ethyl acetate. The combined extracts are dried (MgSO₄), evaporatedto give crude oil which is purified by chromatography on silica gelusing methylene chloride:methanol (100:2) as eluent to yield4-[alpha(4-cyanophenyl)-3-pyridylmethyl]-benzonitrile which is convertedto the hydrochloride salt in ether, m.p. 120°-125° dec., the compound ofExample 21.

EXAMPLE 45

To a mixture of 148.5 g of4-[alpha-chloro-(3-pyridylmethyl)]benzonitrileand 560 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone under anargon atmosphere 190 ml of N,N-diisopropyl-ethyl-amine are added at roomtemperature. The clear solution is cooled to 20° C. and while stirring66.7 g of imidazole are added. Then the mixture is heated to 140° C. Thereaction mixture is concentrated in vacuo at 90° C. and the residue isdissolved in 2.5 1 of ethyl acetate. Then 1 1 of an ammonia solution isadded and the mixture is extracted three times with 0.5 1 of 2N ammoniaand once with 0.5 1 of brine. The organic layers are dried, filtered andconcentrated under reduced pressure. The residue is evaporated at 60° C.under high vacuum and then chromatographed on silica gel. Eluation withmethylene chloride/methanol 95:5, for example, yields4-[alpha-(3-pyridyl)-1-imidazolylmethyl]benzonitrile, IR(CN):2237 cm⁻¹ ;M/e: 260.

The starting material can be prepared, for example, as follows:

A mixture of 22.5 1 of methylene chloride and 3030 ml of tert-butylamineis cooled to 0° C. Then a solution of 3 kg of 4-bromo-benzoyl chloridein 15 1 of methylene chloride is added in portions. The mixture iscooled to 0°-5° C. and then stirred over night at room temperature. Thereaction mixture is filtered and the filtrate washed with 5 1 ofmethylene chloride, three times with 5 1 of 3 N HCl, twice with 4 1 ofNaHCO₃ and twice with 2 l of brine. The organic layer is dried over Na₂SO₄ and evaporated. The crude crystals are stirred with 8 l of ether for30 minutes and the mixture is cooled to 0° C. and filtered. Thus4-bromo-N-tert-butyl-benzamide is obtained in form of white crystals,m.p.133°-134° C.

A solution of 256.2 g of 4-bromo-N-tert-butyl-benzamide in 4.4 1 oftetrahydrofuran is cooled to -78° C. and under an argon atmosphere 1.3 1of n-butyl lithium in hexane (1.6 moles) are added slowly whilestirring. Then first a solution of 93.8 ml of pyridin-3-carboxaldehydein 440 ml of tetrahydrofuran are added and after the reaction isfinished 1 l of a saturated ammonium chloride solution is added. Thetemperature is allowed to go up to +5° C. and 1 ; of ether is added. Thereaction mixture is washed with 500 ml of ether and 500 ml of water. Theorganic layer is washed twice with 1.5 l of water and once with 1.5 l ofbrine. The organic layer is dried and evaporated. The residue ischromatographed over silica gel. Eluation with methylenechloride/methanol 9:1 yields 4-[alpha-hydroxy-(3-pyridylmethyl)]-N-tert-butyl-benzamide, m.p. 142°-144° C.

To 1.1 l of sulfuryl chloride a suspension of 568.8 g of4-[alpha-hydroxy-(3-pyridylmethyl)]-N-tert-butyl-benzamide in 2.5 1 ofmethylene chloride is added at a bath temperature of 100° C. whilestirring. The solvent is distilled off. After the formation of gas isfinished, the reaction product is evaporated at 40° C. Accordingly,4-[alpha-chloro-(3-pyridyl)-methyl]benzonitrile is obtained, m.p.162°-165° C.

EXAMPLE 46

232 g of 4-[alpha-(3-pyridyl)-1-imidazolyl-methyl]benzonitrile aredissolved in 8 l of ethanol at 0° C. 890 ml of 2N sulfuric acid areadded in portions. The reaction product is filtered off, washed with 2 lof ethanol and then with 1 l of hexane. The residue is concentrated invacuo, dried at 50° C. and chromatographed on silica gel. Eluation withmethylene chloride/methanol/ammonia 70:5:0.1 yields the sulfate salt of4-[alpha-(3-pyridyl)-1-imidazolylmethyl]benzonitrile, m.p. 242°-244° C.

EXAMPLE 47

Preparation of 10,000 tablets each containing 0.5 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-                                                          5.00     g                                           benzonitrile hemisuccinate                                                    Lactose                  2,535.00 g                                           Corn starch              125.00   g                                           Polyethylene glycol 6,000                                                                              150.00   g                                           Magnesium stearate       40.00    g                                           Purified water           q.s.                                                 ______________________________________                                    

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance, lactose, magnesium stearate and half of thestarch are mixed in a suitable mixer. The other half of the starch issuspended in 65 ml of water and the suspension is added to the boilingsolution of the polyethylene glycol in 260 ml of water. The paste formedis added to the powders, which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35°,broken on a screen with 1.2 mm openings and compressed into tablets,using concave uppers bisected.

Analogously tablets are prepared containing the other compoundsdisclosed and exemplified herein, e.g.4-[alpha(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]-benzonitrile.

EXAMPLE 48

Preparation of 1,000 capsules each containing 1.0 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        4-[alpha-(3-pyridyl)-1-imidazolylmethyl]-benzonitrile                                                     1.0    g                                          sulfate                                                                       Lactose                     216.0  g                                          Modified starch             80.0   g                                          Magnesium stearate          3.0    g                                          ______________________________________                                    

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance is placed in a suitable mixer and mixed firstwith the magnesium stearate, then with the lactose and starch untilhomogeneous. No 2 hard gelatin capsules are filled with 300 mg of saidmixture each, using a capsule filling machine.

Analogously capsules are prepared, containing the other compoundsdisclosed and exemplified herein, e.g.4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methy]benzonitrile.

What is claimed is:
 1. A method of delaying proestrus and estrus andinhibiting proestrus in the anestrus animal which comprisesadministering to a female animal in need thereof an effective amount ofa compound of the formula ##STR16## wherein R and R_(o) representhydrogen or lower alkyl; or R and R_(o) located on adjacent carbon atomsand together when combined with the benzene ring to which they areattached form a naphthalene or tetrahydronaphthalene ring; R₁ representshydrogen; R₂ represents hydrogen, lower alkyl, lower alkenyl, aryl,aryl-lower alkyl, C₃ -C₆ -cycloalkyl, or C₃ -C₆ -cycloalkyl-lower alkyl;or R₁ and R₂ combined represent lower alkylidene, or mono- ordi-aryl-lower alkylidene; R₁ and R₂ combined also represent C₄ -C₆-straight chain alkylene, lower alkyl-substituted-C₄ -C₆ -straight chainalkylene or ortho phenylene bridged-C₂ -C₄ -straight chain alkylene toform with the carbon atom attached thereto a corresponding unsubstitutedor lower alkyl-substituted or benzo-fused 5, 6 or 7-membered ring; Wrepresents 1-imidazolyl or 1-imidazolyl substituted by lower alkyl; arylwithin the above definitions represents phenyl or phenyl substituted byone or two substituents selected from lower alkyl, lower alkoxy,hydroxy, lower alkanoyloxy, aroyloxy, nitro, amino, halogen,trifluoromethyl, cyano, carboxy, carboxy functionalized in form of apharmaceutically acceptable ester or amide, lower alkanoyl, aroyl, loweralkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl or N,N,-di-loweralkylsulfamoyl; and aryl within the above definitions also represents2-, 3-, or 4-pyridyl, or a said heterocyclic radical monosubstituted bylower alkyl, lower alkoxy, cyano or halogen; and aroyl within the abovedefinitions represents benzoyl or benzoyl substituted by lower alkyl,lower alkoxy, halogen or trifluoromethyl; or of a veterinarilyacceptable salt thereof; or of a veterinary composition comprising asaid compound in combination with one or more veterinarily acceptablecarriers
 2. A method according to claim 1 wherein proestrus and estrusin a female canine is delayed or wherein proestrus in female canine isinhibited.
 3. A method according to claim 1 which comprisesadministering to female canine in need thereof an effective amount of acompound of the formula ##STR17## wherein R₁ ' represents hydrogen; R₂ 'represents hydrogen, lower alkyl, phenyl, 2-, 3- or 4-pyridyl or benzyl;or R₂ ' represents phenyl or benzyl, each monosubstituted on the phenylring by cyano, lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy,aroyloxy, nitro, halogen, trifluoromethyl, lower alkanoyl, aroyl, loweralkylsulfonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl,sulfamoyl, N-mono- or N,N-di-lower alkylsulfamoyl; or R₁ ' and R₂ 'combined represent together lower alkylidene, benzylidene ordiphenylmethylidene; or R₁ ' and R₂ ' combined represent together C₄ -C₆straight chain alkylene; R₃ represents hydrogen or lower alkyl; or aveterinarily acceptable salt thereof; or of a veterinary compositioncomprising said compound in combination with one or more veterinarilyacceptable carriers.
 4. A method according to claim 1 which comprisesadministering to female canine in need thereof an effective amount of acompound of the formula ##STR18## wherein R₂ ' represents 3-pyridinyl,p-cyanobenzyl or p-cyanophenyl; or a veterinarily acceptable saltthereof; or of a veterinary composition comprising said compound incombination with one or more veterinarily acceptable carriers.
 5. Amethod according to claim 1 which comprises administering to femalecanine in need thereof an effective amount of4-[alpha-(3-pyridinyl)-1-imidazolylmethyl)]benzonitrile or of aveterinarily acceptable salt thereof; or of a veterinary compositioncomprising said compound in combination with one or more veterinarilyacceptable carriers.
 6. A method according to claim 1 which comprisesadministering to female canine in need thereof an effective amount of4-[alpha-(4-cyanophenyl)-1-imidaolylmethyl]benzonitrile or of aveterinarily acceptable salt thereof; or of a veterinary compositioncomprising said compound in combination with one or more veterinarilyacceptable carriers.